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Dodiya, Bhavesh L., 2011, “Studies on Chemical Entities of Therapeutic

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“STUDIES ON CHEMICAL ENTITIES OF

THERAPEUTIC INTEREST”

A THESIS

SUBMITTED TO THE

SAURASHTRA UNIVERSITY

FOR THE DEGREE OF

Doctor of Philosophy IN

THE FACULTY OF SCIENCE (CHEMISTRY)

BY Bhavesh L. Dodiya

UNDER THE GUIDANCE

OF

Prof. H. S. Joshi DEPARTMENT OF CHEMISTRY

(DST-FUNDED, UGC-SAP SPONSORED),

SAURASHTRA UNIVERSITY

(Re-Accredited Grade B by NAAC, CGPA 2.93),

RAJKOT - 360 005

(GUJARAT) INDIA

MAY-2011

Gram: UNIVERSITY Phone: (R) 0281-2584221 Fax: 0281-2577633 (O) 0281-2578512

SAURASHTRA UNIVERSITY University Road Rajkot - 360 005

Prof. H. S. Joshi Residence: M.Sc., Ph.D., F.I.C.S. B-1, Amidhara Appartment, Professor, 2- Jalaram Plot, Department of Chemistry University Road, Rajkot - 360 005 No. GUJARAT (INDIA) Date: - -2011 Statement under O. Ph. D. 7 of Saurashtra University The work included in the thesis is my own work under the supervision of Prof. H.

S. Joshi and leads to some contribution in chemistry subsidized by a number of

references.

Date: - -2011 (Bhavesh L. Dodiya) Place: Rajkot This is to certify that the present work submitted for the Ph. D. Degree of

Saurashtra University by Bhavesh L. Dodiya his own work and leads to advancement in

the knowledge of chemistry. The thesis has been prepared under my supervision.

Date: - -2011 Prof. H. S. Joshi Place : Rajkot Professor Department of Chemistry Saurashtra University

Rajkot-360005

ACKNOWLEDGEMENT

First and foremost, I wish to pay my sincere homage to the Lord Shiva for

making me capable of doing all that I propose, the work leading to my Ph. D. thesis

submission is one of them.

I would like to express my sincere gratitude to my supervisor Prof. H. S. Joshi

for accepting me as his research student and who made this research a success. It is

with Dr. Joshi’s enthusiasm and integral view on research combined with his

willingness to provide quality chemistry and not less that kept me going and I wish to

say thank you sir. Besides being a wonderful Supervisor, Dr. Joshi is as close as family

and a very good friend and I am deeply honored to have wonderful person like him in

my life. I wish to say thank you so much again for all the help you offered over the

years both in and out of my academic life.

I also owe to Dr. P. H. Parsania, Professor and Head, Department of

Chemistry, Prof. Anamik Shah and Dr. Y. T. Naliapara as I have been constantly

benefited with their lofty research methodology and the motivation as well as their

affectionate. I am thankful to the all staff members of the Department of Chemistry

for their relevant support to me. I am also thankful to Mr. Harshadbhai Joshi for

their kind support. I express my grateful tribute to Department of Chemistry,

Saurashtra University for providing me the excellent laboratory facilities for

accomplishing this work. I also thanks to University Grants Commission for finding

me as Meritorious Research Fellow which is really an achievement and helpful task for

me.

From bottom of heart I specially thanks to my seniors Dr. N. M. Dodiya, Dr.

D. H. Purohit, Dr. Paresh Zalavadiya, Dr. Vijay Ram, Dr. Satish Tala, Dr. Jignesh

Akbari, Dr. Kapil Dubal and Tejas Parmar for their selfless help, moral support and

guidance during my Ph. D. work. I heartily express special thanks to Dr. Govind &

Ila, Mr. Piyush Vekariya and Mr. Gaurang Pandya, for their unlimited help to me.

An endeavor such as a Ph. D. is impossible to accomplish without the generous

help and support of seniors and colleagues Dr. Kaushik Joshi, Haresh Ram, Ramesh

Nandaniya and Ranjit Pada by whom I was inspired for my doctoral work.

Words are inadequate to thank my most beloved friend and colleagues Renish

Ghetiya, Dr. Mehul Bhatt, Abhay Bavishi and Vipul (Odich) who was always helping

me in all situations.

I am very much thankful to him for his technical guidance and comprehensive

exchange of ideas during the course of my research work. I am very much thankful to

Dr. Shailesh, Dr. Shrey, Dr. Amit, Dr. Nayan, Dr. Rahul, Dr. Ravi, Ashish, Jignesh,

Suresh, Ritesh, Pooja, Rizwan, Leena, Bharat, Bhavin, Ravi, Dhiru, Hardev,

Harshad, Manisha, Ashish(Master), Hitesh, Mrunal, Ramani, Ladwa, Mahesh, Anil,

P.P., Gami, Naimish, Rakesh, Deepti, Chintan, Bipin, Vipul and Dangar.

I get this achievement with tremendous support and cooperation of my friends

Karshanbhai, Hiren, Yogesh, Anil, Jayesh, Nilesh, Gatur, Sidhu, Pravin, Mepal,

Pedu, Nikhil, Bipin, Rakesh, Dinesh, Pankaj and Joshi thank you so much to be such

a wonderful friend and fill my life with full of joy and stay with me whenever I

needed.

First and foremost I want to pay all my homage and emotions to my beloved

grandmother late. Kurayben and Bhabhu Raniben. Most venerated my elder bhai &

bhabhi Arjanbhai-Kamarabhabhi, whose blessing this task would not have been

accomplished. I bow my head with utter respect to them for their continuous source of

inspiration, motivation and devotion to me.

Who have given us everything that we possess in this life? The life itself is their

gift to us, so I am at loss of words in which to own my loving mother Smt. Kariben

and most esteemed father Shri Lakshmanbhai and most venerated brother

Narsinhbhai-Lasubhabhi, Kalubhai-Nathibhabhi. I am very much grateful to My

Sister Maniben, Rasilaben and Harshaben for their love, affectionate and caring. I am

also obliged to my younger brother Rahul and my cute nephews & nice Rushi, Rohit,

Hiren, Keval, Dhaval, Hetal, Kajal, Kinjal. Through the stress and strain of this

study, my friend and wife Mital has encouraged me to reach my destination.

(Bhavesh L. Dodiya)

CONTENTS

SYNOPSIS……………………………………………………………………………………..1 STUDIES ON CHEMICAL ENTITIES OF THERAPEUTIC INTEREST PART-A: STUDIES ON INDOLE-2-CARBOXYLIC ACID DERIVATIVES

1. Introduction………………..............................................................................................8

2. Therapeutic Importance……………………………………………………………...…13

3. References………………………………………………………………………………19

PART-I: STUDIES ON INDOLE-3-YL-GLYOXYLAMIDE DERIVATIVES

1. Introduction……………………………………………………………………………..24

2. Therapeutic Importance………………………………………………………………...28

Section-I

Synthesis and biological evaluation of 3-[N,N-Dialkylamine(oxo)acetyl]-1-propyl-1H-indole-

2-carboxylic acids

1. Reaction scheme………………………………………………………………………...32

2. Experimental section…………………………………………………………………....33

3. Analytical data………………………………………………….………………………35

4. Spectral study…………………………………………………………………………...37

5. Antimicrobial activity………………………………………………………………...…42

6. References….……………………………………………………………………….…..45

PART-II: STUDIES ON IMIDAZOLONE DERIVATIVES

1. Introduction……………………………………………………………………….…….48


Section-I

Synthesis and biological evaluation of N-[(4Z)-4-Arylidene-5-oxo-2-phenyl-4,5-dihydro-1H-

imidazol-1-yl]-1H-indole-2-carboxamides.

1. Reaction scheme…………………………………………………………………..…….52


3. Analytical data……………………………………………………………………….…55

4. Spectral study…………………………………………………………………………...57


6. References……………………………………………………………………….….......63

PART-III: STUDIES ON OXADIAZOLE DERIVATIVES

1. Introduction……………………………………………………………………….…….65


Section-I

Synthesis and biological evaluation of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-propyl-1H-indoles.

1. Reaction scheme……………………………………………………………………..….70

2. Experimental section………………………………………………………………...….71

3. Analytical data……………………………………………………………………….…73

4. Spectral study…………………………………………………………………………...75

5. Antimicrobial activity…………………………………………………………...………80

6. References………………………………………………………………………………81

PART-B: STUDIES ON IMIDAZO[1,2-a]PYRIDINE DERIVATIVES

1. Introduction……………………………………………………………………….…….84

2. Therapeutic Importance………………………………………………………………...87

3. References………………………………………………………………………………91

PART-I: STUDIES ON IMIDAZO[1,2-a]PYRIDINE-3-YL-GLYOXYLAMIDE

DERIVATIVES

1. Introduction……………………………………………………………………….…….94

2. Therapeutic Importance…………………………………………………………………95

Section-I

Synthesis and biological evaluation of 1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-

3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-diones.

1. Reaction scheme………………………………………………………………………...96

2. Experimental section……………………………………………………………………97

3. Analytical data……………………………………………………………………….…100

4. Spectral study…………………………………………………………………………...102


6. References………………………………………………………………………………108

PART-II: STUDIES ON MANNICH BASE DERIVATIVES

1. Introduction……………………………………………………………………….…….109


Section-I

Synthesis and biological evaluation of 2-(4-Fluorophenyl)-6-methyl-3-(N,N-dialkylamine-4-

ylmethyl)imidazo[1,2-a]pyridines.

1. Reaction scheme………………………………………………………………………...114

2. Experimental section………………………………………………………………...….115

3. Analytical data ………………………………………………………………………....117

4. Spectral study…………………………………………………………………………...119


6. References………………………………………………………………………………125

PART-III: STUDIES ON BIS-IMIDAZO[1,2-a]PYRIDIN DERIVATIVES

3. Introduction…………………………………………………………………….……….127


Section-I

Synthesis and biological evaluation of 2-(4-Flurophenyl)-3-((2-(4-flurophenyl)-6-methylH-

imidazo[1,2-a]pyridine-3-yl)(aryl)methyl)-6-methylH-imidazo[1,2-a]pyridines.

1. Reaction scheme………………………………………………………………………...132


3. Analytical data……………………………………………………………………….…135

4. Spectral study………………………………………………………………………..….137


6. References………………………………………………………………………………143

PART-C: STUDIES ON THIOPHENE DERIVATIVES

1. Introduction……………………………………………………………………………..145


3. References………………………………………………………………………………149

PART-I: STUDIES ON PYRAZOLINE DERIVATIVES

1. Introduction……………………………………………………………………….…….151


Section-I

Synthesis and biological evaluation of 1H-Indol-2-yl[3-aryl/thiophene-5-(thiophen/aryl-2-yl)-

4,5-dihydro-1H-pyrazol-1-yl]methanones.

1. Reaction scheme………………………………………………………………………...159


3. Analytical data……………………………………………………………………….…163

4. Spectral study………………………………………………………………………..….167


6. References………………………………………………………………………………173

PART-II: STUDIES ON PYRIMIDINE DERIVATIVES

1. Introduction……………………………………………………………………….…….178


Section-I

Synthesis and biological evaluation of 2-Methyl-5-aryl/thiophen-7-(thiophen/aryl-2-

yl)pyrido[2,3-d]pyrimidin-4(3H)-ones.

1. Reaction scheme………………………………………………………………………...184


3. Analytical data……………………………………………………………………….…187

4. Spectral study…………………………………………………………………………...191


6. References………………………………………………………………………………197

List of publication…………………………………………………………………………………….....199

SYNOPSIS

Studies on chemical…

Synopsis 1

The research work incorporated in the thesis with the title “STUDIES ON

CHEMICAL ENTITIES OF THERAPEUTIC INTEREST” has been described as

under.

PART-A : STUDIES ON INDOLE-2-CARBOXYLIC ACID DERIVATIVES

PART-B : STUDIES ON IMIDAZO[1,2-a]PYRIDINE DERIVATIVES

PART-C : STUDIES ON THIOPHENE DERIVATIVES

PART-A : STUDIES ON INDOLE-2-CARBOXYLIC ACID DERIVATIVES

Nowadays, the entire pharmaceutical industry is faced with the challenge of

increasing productivity and innovation. The major hurdles are the increasing costs of

research and development and a simultaneous stagnating number of new chemical entities

(NCEs). So the primary goal of the our research work is to find and develop new

chemical entities (NCEs)

Indole nucleus possesses remarkable pharmaceutical importance and biological

activities, some of their derivatives occur as natural products, amino acid, hormones etc.

In animals serotonin is a very important neurotransmitter in the central nervous system

and also plays a vital role in the cardiovascular and gastrointestinal system. Many indole

derivatives are used as pharmaceuticals and highly selective medicines which are in

current use. In view of our on going interest in the synthesis of some new potentially

bioactive indole derivatives have been described as under.


The synthesis of compounds incorporating indole-3-yl-glyoxylamide has been

attracted widespread attention due to their diverse pharmacological properties like

anticancer, anti-inflammatory, antibiotic, antifungal, herbicidal, antitubercular etc. To

approach this goal syntheses of some indole-3-yl-glyoxylamides have been undertaken,

which have been described as under.

SECTION-I: Synthesis and biological evaluation of 3-[N,N-Dialkylamine(oxo)

acetyl]-1-propyl-1H-indole-2-carboxylic acids.


Synopsis 2

N

O

OH

OOR

CH3 R = Seco. amine

Type (I)

Indole-3-yl-glyoxylamide derivatives of Type (I) have been synthesized by the

condensation of 1-propyl-1H-indole-2-carboxylic acid with oxalyl chloride and different

secondary amine in the presence of DCM.


The discovery of imidazolone as potent biologically active agent has led to the

exploration of large number of structural variants, containing imidazolone moiety as an

invariable ingredient. Its derivative have shown various biologically activities such as

anathematic, antimicrobial, antihistamine, anti-inflammatory, antibacterial etc. in order to

develop therapeutically important compounds, it was consider of interest to synthesize

some imidazolones shown as under.

SECTION-I: Synthesis and biological evaluation of N-[(4Z)-4-Arylidene-5-oxo-2-

phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-indole-2-carboxamides.

NH

NH

O

NN

OR

R= Aryl

Type (II)

The synthesis of imidazolones of Type (II) have been under taken by the reaction

of 1H-indole-2-carbohydrazide with substituted azalactone which in turn have been

prepared by well known Erlenmeyer azalactone synthesis.


Synopsis 3


1,3,4-Oxadiazoles are associated with broad spectrum of pharmacological activity

like anesthetic, hypnotic, antibacterial, hypoglycemic and antifungal. These valid

observations promoted us to synthesize 1,3,4-oxadiazole derivatives with better

therapeutic value which have been described as under.

SECTION-I: Synthesis and biological evaluation of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-

1-propyl-1H-indoles.

N

CH3

N

O

N

R

R=Aryl

Type (III)

The oxadiazole derivatives of Type (III) have been synthesized by the

condensation of 1-propyl-1H-indole-2-carbohydrazide with various aromatic acids in the

presence of POCl3.

PART-B : STUDIES ON IMIDAZO[1,2-a]PYRIDINE DERIVATIVES

Heterocyclic compounds bearing imidazo[1,2-a]pyridine ring system are endowed

with variety of biological activities. Our strategy is based on to develop a new bioactive

entity especially with pharmacological activities bearing heterocyclic ring system.

Literature survey reveals that nitrogen containing heterocyclic compounds like

imidazo[1,2-a]pyridines have received considerable attention in medicinal science due to

their biological and pharmacological activities like anti-inflammatory, antitumor, calcium

channel blocker, hypnotic, sedative, antimicrobial, antitubercular, CNS depressant,

antithyroid and many other therapeutic activities.

These valid observations led us to design and synthesize some heterocycles like

glyoxylamide, mannich bases, bis-imidazo[1,2-a]pyridine etc., bearing imidazo[1,2-

a]pyridine nucleus, which have been described as under.


DERIVATIVES


Synopsis 4

Imidazo[1,2-a]pyridine-3-yl-glyoxylamide derivatives have been found to be

potent drug in pharmaceutical and possess a wide range of pharmacological activities

such as anticancer, anticonvulsant, hypnotic, antithyroid, anti-inflammatory etc. It

appeared of interest to design and synthesize imidazo[1,2-a]pyridine-3-yl-glyoxylamide

derivative, which have been describe as under.

SECTION-I: Synthesis and biological evaluation of 1-[2-(4-Fluorophenyl)-6-

methylimidazo[1,2-a]pyridin-3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-diones.

N

NF

CH3O

R

O

R= Seco. amine

Type (IV)

Imidazo[1,2-a]pyridine-3-yl-glyoxylamide derivatives of Type (IV) have been

synthesized by the condensation of 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine

with oxalyl chloride and different secondary amine in the presence of DCM.


Compound containing bridge N-atom exhibit pronounced pharmacological

activities. Mannich base derivatives with bridge N-atom have been found to potent drug

in medicine science and possess a wide range of therapeutic activities like

antihypertensive, antidepressant, anticholestemic, antifungal etc. by consideration this

valid observations, to approach this goal we have synthesize some new mannich bases,

which have been shown as under.

SECTION-I: Synthesis and biological evaluation of 2-(4-Fluorophenyl)-6-methyl-3-

(N,N-dialkylamine-4-ylmethyl)imidazo[1,2-a]pyridines.

N

N

CH3

F

R R= Seco. amine

Type (V)


Synopsis 5

Mannich bases of Type (V) have been synthesized by the condensation of 2-(4-

fluorophenyl)-6-methylimidazo[1,2-a]pyridine with different secondary amines and

formaldehydes in the presence of acid catalyst.


Bis imidazo[1,2-a]pyridine derivatives are important intermediates in organic

synthesis, especially in the synthesis of biologically active and medicinally useful agents.

For instance, they are widely used in the synthesis of cyclin-dependent kinases (CDK)

inhibitors, sleep inducers, anticonvulsant agents, antiviral agents etc. The synthesis of

some new potentially bioactive bis imidazo[1,2-a]pyridine derivatives have been

undertaken.

SECTION-I: Synthesis and biological evaluation of 2-(4-Flurophenyl)-3-((2-(4-

flurophenyl)-6-methylH-imidazo[1,2-a]pyridine-3-yl)(aryl)methyl)-6-methylH-

imidazo[1,2-a]pyridines.

N

N

CH3

F

N

NF

CH3R

R=Aryl

Type (VI)

Bis imidazo[1,2-a]pyridine derivatives of Type (VI) have been synthesized by the

condensation of the 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine with different

aryl aldehyde and sodium acetate.

PART-C : STUDIES ON THIOPHENE DERIVATIVES

Thiophen nucleus represents important building blocks in both natural and

synthetic bioactive compounds, which have been shown to possess diverse therapeutic

activities. Our works are paying attention on introduction of chemical multiplicity in the

molecular frame work, in order to synthesizing active molecules of widely different

composition. Literature assessment reveals that sulfur containing heterocyclic compounds

has been shown to have a broad range of important biological and pharmacological

activities such as anti-HIV, antitubercular, antimicrobial, anticonvulsant, anticancer,


Synopsis 6

antiviral etc. Considering the increasing importance of thiophene nucleus, we have

undertaken the synthesis of some new pyrazoline and pyrimidine derivatives bearing

thiophene nucleus, which have been described as under.


In the present chapter, the efforts have been made for the synthesis of pyrazoline

derivatives. Substituted pyrazoline derivatives have drawn considerable attention of the

chemist due to their good pharmacological activities like antibacterial, anticonvulsant,

analgesic etc. with a view to getting better therapeutic agent and to evaluate

pharmacological profile, different types of pyrazoline derivatives have been prepared

which have been described as under.

SECTION-I: Synthesis and biological evaluation of 1H-Indol-2-yl[3-aryl/thiophene-

5-(thiophen/aryl-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.

NN

ONH

R1

R

R = thiophene/aryl

R1 = aryl/thiophene

Type (VII)

Pyrazoline derivatives of Type (VII) have been synthesized by the

cyclocondensation of the 1H-indole-2-carbohydrazide and different substituted chalcones

under acidic condition.


The chemistry of pyrimidine and its derivatives has been studied for over a

century due to their diverse biological activities. Due to formal isoelectronic relationship

with purines, the pyrido[2,3-d]pyrimidine ring system is of special biological interest. It

has numerous pharmacological and medicinal applications viz, antitumour,

immunodilator, tuberculosis, antiallergic and radioprotective.


Synopsis 7

SECTION-I: Synthesis and biological evaluation of 2-Methyl-5-aryl/thiophen-7-

(thiophen/aryl-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-ones.

N R1

R

NH

N

O

CH3 R = thiophen/aryl

R1 = aryl/thiophen

Type (VIII)

The synthesis of pyrido[2,3-d]pyrimidines of Type (VIII) was achieved by acid

catalysed cyclocondensation of 2-amino-6-aryl/thiophene-4-(thiophene/aryl-2-

yl)pyridine-3-carbonitrile with glacial acetic acid.

The constitution of all the synthesized compounds have been characterized by

using elemental analysis, FT-IR, 1H NMR and 13C NMR spectroscopy and further

supported by mass spectroscopy. Purity of all the compounds have been checked on thin

layer chromatographic plate and HPLC technique.

All the compounds have been evaluated for their antibacterial activity towards

Gram +ve and Gram -ve bacterial strains and antifungal activity towards Aspergillus

niger at a concentration 40 µg/ml. The biological activities of the synthesized compounds

have been compared with standard drugs.

Part – A

Introduction

Studies on Indole-2-carboxylic acid Derivatives


Indole derivatives… 8

INTRODUCTION

Indole (2,3-benzopyrrole, ketole, 1-benzazole; C8H7N) is an aromatic heterocyclic

organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring

fused to a five-membered nitrogen-containing pyrrole ring. The participation of the

nitrogen lone pair electron in the aromatic ring means that indole is not a base, and it does

not behave like a simple amine.

Indole is a solid at room temperature. It can be produced by bacteria as a

degradation product of the amino acid tryptophan. It occurs naturally in human faces and

has an intense facial odor. At very low concentrations, however, it has a flowery smell,

and is a constituent of many flower scents (such as orange blossoms) and perfumes. It

also occurs in coal tar.

NH1

2

345

67

(1)

Indole compounds include the plant hormone Auxin (indolyl-3-acetic acid), the

anti-inflammatory drug indomethacin, the betablocker pindolol, and the naturally

occurring hallucinogen dimethyltryptamine.

The name indole is a portmanteau of the words indigo and oleum, since indole

was first isolated by treatment of the indigo dye with oleum. Indole chemistry began to

develop with the study of the dye indigo. Indigo can be converted to isatin and then to

oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust.1 In

1869, he proposed a formula for indole.2

Certain indole derivatives were important dyestuffs until the end of the 19th

century. In the 1930, interest in indole intensified when it became known that the indole

nucleus is present in many important alkaloids, as well is in tryptophan and auxins, and it

remains an active area of research today.3

The indole skeleton is one of the most attractive frameworks with a wide range of

biological and pharmacological activities.4 This physiologically important nucleus is

abundantly found in therapeutic agents5,6 as well as in natural products. Many researchers

have described synthesis of indole and its derivatives along with its applications in

literature.7

http://en.wikipedia.org/wiki/Auxin

http://en.wikipedia.org/wiki/Indomethacin

http://en.wikipedia.org/wiki/Betablocker

http://en.wikipedia.org/wiki/Pindolol

http://en.wikipedia.org/wiki/Dimethyltryptamine

http://en.wikipedia.org/wiki/Portmanteau_word

http://en.wikipedia.org/wiki/Indigo_dye

http://en.wikipedia.org/wiki/Oleum

http://en.wikipedia.org/wiki/Indigo_dye

http://en.wikipedia.org/wiki/Isatin

http://en.wikipedia.org/wiki/Oxindole

http://en.wikipedia.org/wiki/Adolf_von_Baeyer

http://en.wikipedia.org/wiki/Zinc

http://en.wikipedia.org/wiki/Indole#cite_note-baeyer1869-2

http://en.wikipedia.org/wiki/Alkaloid

http://en.wikipedia.org/wiki/Tryptophan

http://en.wikipedia.org/wiki/Auxin

http://en.wikipedia.org/wiki/Indole#cite_note-vanorder1942-3



SYNTHETIC ASPECT

Various methods for the preparation of indole derivatives have been cited in

literature, some of them are as under.

1. B. George8 has reported one-pot microwave assisted synthesis of indole from

phenylhydrazine and pyruvic acid.

NHNH2 O

HOOC

CH3

ZnCl2PCl5 N

H

+

2. N. Sakai et al.9 have cyclized 2-ethynylanilines by indium as catalyst and

produced various indole derivatives in good yields for substrates having an alkyl

or aryl group on the terminal alkyne.

NH

R3

R1

R2

5 mol -% in Br3

toluene, reflux 5-20 hR

1

NR

3

R2

3. Rhodium (II) perfluorobutyrate-mediated decomposition of vinyl azides

allows rapid access to a variety of complexes of indole was prepared by B.

J. Stokes et al.10

N3

O

OCH3

R1 R

1

NH

O CH3

O

3-5 mol-%

toluene, 60 oC, 16 h

Rh2(OCOC3F7)4

4. Y. Du and coworkers11 have been synthesized various N-arylated and N-alkylated

indoles and pyrrole-fused aromatic compounds by a phenyliodine

bis(trifluoroacetate) (PIFA)-mediated intramolecular cyclization.

R3

NHR

1

R2

EWG

R1

NR

3

R2

EWG

1.3 eq. PhI(O2CCF3)2(PIFA)

CH2Cl2, RT, 30 min



5. Microwave-assisted synthesis of indole derivatives in water via

cycloisomerization of 2-alkynylanilines and alkynylpyridinamines promoted by A.

Carpita et al.12,13

NH2

R2

R1 H2O, 200 oC

MW, base/acid saltR

1

NH

R2

6. Synthesis of 2-substituted indoles via palladium-catalyzed domino Heck reaction

with 71 % yield was given by H. Mao et al.14

I

N R1 N

H

R1Pd(OAc)2, PPh3, 120oC

KOBu-t, DMSO

7. D. K. Whelligan and coworkers15 have synthesized two-step aza- and diazaindoles

from chloroamino-N-heterocycles using ethoxyvinylborolane.

NH2

OEtR

1 AcOHR

1

NH

8. One-pot synthesis of indole derivatives from nitroarenes under hydrogenation

condition with supported gold nanoparticles was reported by Y. Yamane et al.16

NO2

R1

NH

R1H2

Au/Fe2O3

9. A mild preparation of substituted indole from simple aromatic precursors using

(trimethylsilyl)diazomethane was reported by L. Zhu et al.17

NHNH2

OTMSCHN2, CS2CO3

MeOH, 60oC



10. E. V. Sadanandan et al.18 have synthesized 4,6,7-trimethoxyindol marine

alkaloids.

OMe

OMeMeO

COOMe

N3

xylenereflux

OMe

OMeMeO N

H

COOMe

11. S. Wagaw et al.19 have reported novel fischer indole synthesis.

NHN

PhPhR

3+

R1

O R2

TsOH.H2O, EtOH

refluxR

3

NH

R1

R2

12. G. A. Kraus and coworkers20 have synthesized indole derivatives under

microwave-assisted conditions with high yields in one-pot reaction.

+PPH3

-Br

N R1

t-BuoKTHF, 25 oC N

H

R1

13. Gold(III)-catalyzed indole derivatives from 2-alkynylanilines in EtOH annulations

at room temperature in good yields was reported by A. Arcadi et al.21

R1

NH2

R2

4 mol-% NaAuCl4.2H2O

EtOH, rtR

1

NH

R2

14. Copper(II)-catalyzed cyclization of 2-ethynylaniline derivatives to indoles can be

carried out in a MeOH was given by K. Hiroya et al.22

NH

R3

SO2R1

R2 Cu(OCOCF3)2

MeOH, rtR

2

N

SO2R1

R3



15. A. Dobbs et al.23 have synthesized indole derivatives from ortho-

bromonitrobenzenes with various vinyl grignard reagents in THF.

BrNO2

R1

+R

2

R3

MgBrTHF, -40 oC

Br

R1

NH

R2

R3

16. One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-

iodoanilines and aldehydes under mild ligandless conditions in DMF was reported

by Y. Jia et al.24

R1

NH

I

R2

+O

R3

H5 mol-% Pd(OAc)2 R

1

N

R3

R2

DABCO, DMF, 85 oC

17. Suzuki-Miyaura coupling of ortho-gem-dihalovinylanilines with boronic acids, of

a Pd(OAc)2 catalyst in the presence of K3PO4·H2O was doccumented by Y. Q.

Fang et al.25

NH2

R1

R2

Br

Br

+ R1

NH

Ar

R2

Ar-B(OH)2

1-5 mol-% Pd(OAc)2

K3PO4.H2O, toluene, 90 oC

18. V. Sridharan et al.26 have synthesized microwave assisted 2-arylindoles in good

yields.

NHR

1

O ArMW

DMFR

1

NH

Ar

19. Lewis acids catalyzed cyclization of methyl phenyldiazoacetates was reported by

L. Zhou et al.27



N R1

COOCH3

N2

Zn(OTf)2

MDC, rt NH

R1

COOCH3

REACTION MECHANISM

The reaction of phenyl hydrazine with an aldehyde or ketone initially forms

phenylhydrazone which isomerizes to the respective enamine. After protonation, a cyclic

sigmatropic rearrangement occurs producing an imine. The resulting imine forms a cyclic

aminoacetal, which under acid catalysis eliminates NH3, resulting in the energetically

favorable aromatic indole.

NHN

NHNH

NHNH

H

NH2NH

H+

NH2NH2- +N

HNH2

HH

-H+H

+

NH

NH3

HH

+-H

+

-NH3NH

Phenylhydrazone Enamine Imine

AminoacetalIndole THERAPEUTIC IMPORTANCE

The indole ring system represents a privileged structure in drug discovery. The

number of bioactive compounds containing this ring system is so vast that the complete

range of their biological activities can be hardly classified.28-30

1. Analgesic31

2. Antiallergic32

3. Antibacterial33

4. Anticonvulsant34

5. Antifungal35

6. Antihistaminic36

7. Anti-inflammatory37

8. Antitumor38



9. Antiviral39

10. β-adrenergic40

11. Diuretic41

12. Insecticidal42

13. Anticancer43

14. Anti HIV44

15. Anti hypertensive45

16. Cardiovascular46

17. Antioxidant47

B. Pelcman et al.48 have synthesized marine sponge pigment fascaplysin (2) from

indole and reported their antimicrobial activity.

NH

N

(2)

M. C. Pirrung et al.49 have synthesized indolylquinones (3) and checked their

activity on the human insulin receptor by demethylasterriquinone B1 (DAQ B1) and its

consequent oral insulin mimetic activity tested in mice by B. Zhang and coworkers.50

DAQ B1 was also subsequently shown to activate the TrkA nerve growth factor receptor

was reported by N. Wilkie and coworkers. 51

O

ONH

NH

OH

OH

(3)

Activities of asterriquinones (4) against HIV protease and HIV reverse

transcriptase have been disclosed by A. Fredenhagen et al.52 and K. Ono et al.53 and also

activity against serine proteases given by U. Mocek et al.54



NH

NH

O

O

OO

RR

R = H, CH3(4)

S. Pasquini et al.55

prepared library of 1,5-disubstituted-3-indole-N-

alkylacetamides as CB2 receptor ligands. Some representatives of CB2 agonists are

compounds AM1241, GW405833, JWH-015 and AM630 possess an indole structure

reported by K. Mackie et al.56 and C. Manera et al.57

N

O

I

NO2

N

N

N

O

O

O

Cl Cl

N

O

N

O

I

N

O

O

AM1241 GW405833 JWH-015 AM630

J. B. Blair et al.58 have synthesized fluorinated indole (5) derivatives.

NH

NR

1

R2

R3

R4

R1 = OH, H, F R2 = H, OCH3

R3 = H, F R4 = H, F(5)

P. Diana et al.59 have synthesized 3,5-bis(3’-indolyl)pyrazoles (6) by cyclization

of diketones and hydrazine monohydrate and evaluated their antitumor properties. The

interest in this class of compounds has been stimulated by both their unique chemical

structure and the wide range of biological properties including antiviral, antimicrobial,

and antitumor activity was given by V. M. Dembitsky et al.60



NH

BrN

NH N

H

Br

(6)

H. Sard et al.61 have synthesized psilocybin analogs (7) and discoved a selective

5-HT2C agonist.

NH

OR N

R = H, P(O)(OH)2

(7)

E. J. Glamkowski et al.62 have synthesized 3-(4-acylaminopiperazin-1-

ylalky1)indoles (8) as potential anti hypertensive agents.

NH

N

NNH

R1

O

R1 = aryl

(8)

M. Banerjee et al.63 have synthesized indole derivatives, such as HIV-1

nonnucleoside reverse transcriptase inhibitor. D. C. Cole et al.64 have tested 5-HT

receptor agonists or antagonists. Q. Shi et al.65 and H. D. H. Showalter et al.66 have

synthesized and tested peroxisome proliferator-activated receptor (PPAR) agonists and

protein tyrosine kinase inhibitors. G. Primofiore and coworkers67 and K. L. Lee et

al.68 have prepared and tested benzodiazepine receptor (BzR) ligands. Human cytosolic

phospholipase A2R inhibitor and blood coagulation factor Xa inhibitor have also been

presented by H. Matter et al.69

J. Holenz et al.70 prepared medicinal chemistry driven approaches toward novel

and selective serotonin 5-HT6 receptor ligands (9).



N

NR

2R

1

R3

NHSR

4O

O

(9)

Preparation and antibacterial activities of indole containg compounds reported by

Y. Yasuo et al.71 T. Bhawana et al.72 have synthesized and tested antimicrobial activity

of indole derivatives. Synthesis and biological screening of some new indole

derivatives doccumented by D. S. Mehta et al.73 and G. S. Gadaginamath et al.74 Potent

antimicrobial activity of indole derivatives against methicillin-resistant Staphylococcus

aureus investigated by R. A. Al-Qawasmeh et al.75 Regioselective synthesis and

biological evaluation of bis(indolyl)methane derivatives as anti-infective agents given

by M. Damodiran et al.76

Discovery of indole inhibitor of cytosolis phospholipase A2α reported by K. L.

Lee et al.77 Y. Kawashima et al.78 have studied structure activity of indole derivatives

with analgesic and anti-inflammatory activities. Synthesis and anti-inflammatory

activity of heterocyclic indole derivatives reported by R. Preeti et al.79 Amido indole

derivatives used in cannabinoid receptor modulators discovered by H. John et al.80

M. G. Bursavich et al.81 have synthesized indole derivatives and tested for PI3

kinase-α and the mammalian target. Synthesis and evaluation of indole derivatives as

antagonists of Wnt/β-catenin, signaling and CLL cell survival reported by J. Guangyi

et al.82 D. A. James and coworkers83 synthesized conjugated indole-imidazole

derivatives, displaying cytotoxicity against multidrug resistant cancer cell lines. C.

Girolamo et al.84 have synthesized derivatives of the new ring system indole with

potent antitumor and antimicrobial activity. B. Emile et al.85 have synthesized

substituted indole derivatives as new class of antineoplastics agent.



Endogenous substances and marketed drugs with indole substructures

NH

NH2

O

OHNH

NH2

OH

NH

NH

O

O

N

O

O

OH

O Cl N

O

O NN

NH

NS

NH OO

Tryptophan 5 - HT Melatonin

Indometacin OndansetronSumatriptan

NH

NHS

S

Brassinin

Thus the important role displayed by indole and its derivatives for various

therapeutic and biological activities prompted us to synthesize some Glyoxylamide,

Imidazolone and Oxadiazole derivatives bearing indole moiety in order to achieve

compounds having better therapeutic activities described as in the following parts.

STUDIES ON INDOLE-2-CARBOXYLIC ACID DERIVATIVES






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Moriguchi, J. Med. Chem., 29(11), 2284-2290 (1986).

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80. H. John, L. Katerina, W. Hong, P. Chennagiri, C. Ping, N. J. Derek, C. Bang-Chi, Z.

Rulin, K. A. Peter, X. Chen, Bioorg. Med. Chem. Lett., 12(17), 2399-2402 (2002).

81. M. G. Bursavich, N. Brooijmans, L. Feldberg, I. Hollander, S. Kim, S. Lombardi, K.

Park, R. Mallon, A. M. Gilbert, Bioorg. Med. Chem. Lett., 20(8), 2586-2590 (2010).

82. J. Guangyi, L. Desheng, Y. Shiyin, C. N. Christina, J. X. Liu, C. A. Dennis, C. B.

Howard, Bioorg. Med. Chem. Lett., 19(3), 606-609 (2009).

83. D. A. James, K. Koya, H. Li, S. Chen, Z. Xia, W. Ying, Y. Wu, L. Sun, Bioorg. Med.

Chem. Lett., 16(19), 5164-5168 (2006).

84. C. Girolamo, A. Anna Maria, B. Paola, D. Patrizia, L. Antonino, P. Alessandra, M.

Chiara, P. Alessandra, M. Paola, M. Carla, J. Med. Chem., 42(14), 2561-2568 (1999).

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405 (1988).

Part – A

(Part – I)

Studies on Indole-3-yl-glyoxylamide Derivatives


Glyoxylamide derivatives… 24

INTRODUCTION

Indole-3-yl-glyoxylamide derivatives are potent biologically active agent has led

to the exploration of large number of structural variants, containing indole-2-carboxylic

moiety as an invariable ingredient so the synthesis of these compounds has become an

important target in current years. The diversity, efficiency and rapid access to small and

highly functionalized organic molecules makes this approach of central current interest in

the construction of compounds library and optimization in drug discovery process.1,2

NH

O

O

N R2R

1

(1)

A new class of indole-3-yl-glyoxylamide derivatives is high affinity agonists at

the benzodiazepine binding site receptors. It has proved a rich source of clinically

effective drugs, particularly anxiolytics, hypnotics and anticonvulsants.

SYNTHETIC ASPECT

Various methods for the preparation of 3-oxoacetamide-1H-indole derivatives and

alkylation of indole have been cited in literature, some of the methods are as under.

ALKYLATION

1. K. T. Potts et al.3 have synthesized 1-methylindole from indole, CH3I and NaNH2

in diethyl ether solution.

NH

CH3I

NaNH2, Et2O NCH3

2. R. S. Davidson et al.4 have reported N-alkylation of indole using phase transfer

catalyst with ultrasound.



NH

N

C6H5CH2Br

PEG methyl ether

3. Potassium carbonate as a base for the N-alkylation of indole in ionic liquid was

prepared by Y. R. Jorapur et al.5

NH

+ Br Ph[bmim][BF4], CH3CN

K2CO3, 110 oC N

Ph 4. Alkylation of indole from potassium hydroxide, alkyl/aryl halide in acetone was

reported by C. A. Marlic et al.6

NH

NR

1

KOH, R1Xacetone

5. Synthesis of N-alkyl substituted indole in presence of sodium hydride in DMF was

documented by S. Roy et al. 7

NH

N

NC

NaH, DMFBr CN

6. Dual nucleophilic catalysis with DABCO for the N-methylation of indoles was

synthesized by W. Shieh et al.8

NH

R1 DABCO, DMF

MDC, 95 oC NR

1

CH3



7. B. Sebastian et al.9 have synthesized selective Ruthenium-catalyzed N-alkylation

of indole by using alcohol.

NH

R1

+ R2

OH 24 h, toluene N

R1

R2

Shvo, PTSA

GLYOXYLAMIDE

8. The use of (NHC)CuI complex in combination with a N-heterocyclic carbene

precursor as catalyst for the double carbonylation of aryl iodides and secondary

amines solves the problem of using the precious metal Pd and phosphine ligands

was reported by J. Liu et al.10

IR

1+ CO + NH

R2

R2

NHC-Cu-ICS2CO3

R1

O

O

N

R2

R2

9. J. Zhua and coworkers11 have given one-pot synthesis of nitrogen-containing

heteroaryl α-keto amides from heteroaryl halides.

R1

Cl + NNC

O R1

O

ON(1) Base, THF

(2) CH3COOH

10. I. Bennacefa et al.12 have synthesized halogenated N,N-dialkylel-(2-phenyl-1H-

indol-3-yl)glyoxylamide derivatives.

NH

NH

O

O

R1

(1) (COCl)2, THF, 0OC

(2) Amine, THF, 0OC

11. R. Gitto et al.13 have synthesized glyoxylamide derivatives containing N-

substituted isoquinoline nucleus.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6THS-4FW7PYJ-7&_user=3932454&_coverDate=05%2F16%2F2005&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1622158140&_rerunOrigin=scholar.google&_acct=C000061812&_version=1&_urlVersion=0&_userid=3932454&md5=a4d5a4d87327a38f48d155f05ed69fde&searchtype=a#implicit0

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TF8-4M7CSJY-4&_user=3932454&_coverDate=11%2F15%2F2006&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1622134535&_rerunOrigin=scholar.google&_acct=C000061812&_version=1&_urlVersion=0&_userid=3932454&md5=74a43fdcd3f3bedbd2a7d197be9054d8&searchtype=a#aff1



N

OCH3

OCH3

R1

OOH

ON

OCH3

OCH3

R1

OR

2

Ocycloalkylamines,HBTU

DMF, TEA, rt

12. One-step synthesis of N-alkyl-2-aryl-2-oxoacetamide derivatives was given by I.

Yavari et al.14

R1

N+

C-

+

CHO

OH

X

OH

XO

O

NHR

2

13. M. Takhi et al.15 have synthesized 3-indolylglyoxamide derivatives.

NH

NH

O

O

Cl

NH

O

O

R1

(COCl)2

THF, 0OCsecondary amine

THF, 0OC

REACTION MECHANISM

NR

..N

+

R

H-

O

Cl O

Cl

N+

R

HO

-

Cl O

Cl

N+

R

H

O

ClO

R1

NHR

2

NR

OCl

O..

NR

OClN

+

O

R2

R1

H-

NR

ON

O

R2

R1



THERAPEUTIC IMPORTANCE

Indole-3-yl-glyoxylamide derivatives have been tested for various

pharmacological activities, which have been summarized as under.

1. Anticancer16

2. Antitumor17

3. Anxiolytic18

4. Anti-HIV19

5. Antiviral20

6. Antimicrobial15

7. Antileishmanial21

8. GABA-A receptor22

9. Antihypertensive23

10. Cardiovascular24

F. D. Settimo et al.25 have studied anxiolytic effects of N,N-dialkyl-2-phenylindol-

3-ylglyoxylamides (2) by modulation of translocator protein promoting neurosteroid

biosynthesis. M. Gavish et al.26 and P. Casellas et al.27 have synthesized indole-3-

glyoxamide derivatives in a variety of biological processes, including calcium

homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation,

apoptosis induction, and regulation of immune functions. G. Primofiore et al.28 have

synthesized N,N-dialkyl-2-phenylindol-3-ylglyoxylamides a new class of potent and

selective ligands at the peripheral benzodiazepine receptor.

NH

N R2R

1

R3

O

OR4

R5

R1 = R2 = (CH2)2CH3

R3 = NO2, CF3, H, F

R4 = H, NO2, OCH3, F, Cl

R5 = H, Cl, CH3(2)

N. A. Meanwell et al.29 have described the discovery of indole-3-glyoxamide (3)

derivatives as the first small molecule inhibitors of the gp120-CD4 interaction (HIV-1

attachment inhibition) that demonstrate potent antiviral activity in cell culture.30



NH

FO

O

N

N

O

(3)

Antibacterial activities of 3-indolylglyoxamide substituent have been explored in

an effort to improve the spectrum and potency of this class of agents by M. Takhi et al.15

X

N

O

ON N

R1

F

NO

O

R4R

3R2

R1 = H, CN, NO2, OCH3, Br

R2 = H, CH3

R3 = H, CH3

X = CH, N(4)

A series of marine alkaloid 8,9-dihydrocoscinamide, (5) its analogues and

indolylglyoxylamide derivatives have been synthesized and screened for their in vitro

antileishmanial activity profile in promastigote and amastigote models by L. Gupta et al.21

N

O

O

NH

N

R1

R2

R1 = R

2 = CH3 = SO2Ph

(5)

I. Collins et al.31 have synthesized new class of N-(indol-3-ylglyoxylyl)piperidines

(6) are high affinity agonists at the benzodiazepine binding site of human GABA-A

receptor ion-channels, with modest selectivity for receptors containing the α1.



NH

O

O

NO

R1

R1 = OCH2Ph, NHCH2Ph, N(CH3)CH2Ph

(6)

G. Primofiore and coworkers32 have synthesized N-(arylalkyl)indol-3-

ylglyoxylylamides (7) targeted as ligands of the benzodiazepine receptor, as well as

biological evaluation and molecular modeling analysis of the structure activity

relationships reported by them.

NH

R1

O

O

NHR

2

R3

(7)

V. W. Pike et al.33 have evaluated novel N-methyl-2-phenylindol-3-ylglyoxyl-

amides (8) as a new chemo type of 18 kDa translocator protein-selective ligand suitable

for the development of positron emission tomography radioligands.

NCH3

NO2

O

O

NnPr

nPr

(8)

Preparation of 2-[5-[[(6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl]amino]-1H-

indol-3-yl]-N,N-dimethyl-2-(oxo)acetamide (9) compounds as 5-HT6 receptor modulators

for use in medicaments was reported by M. V. Ramon et al.34



NH

O

O

NCH3 CH3

NHSO

ON

NCl

S

(9) W. Tao and coworkers35 have evaluated indole to azaindoles leading to the

discovery of 1-(4-Benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-

yl)ethane-1,2-dione as a antiviral activity in HIV-1 infected subjects. J. Wang and

coworkers36 have modified structure-activity relationship of a small molecule HIV-1

inhibitor targeting the viral envelope glycoprotein gp120. M. Pascal et al.37 have

synthesized N-aryl(indol-3-yl)glyoxamides as antitumor agents.

Literature survey reveals that the compounds bearing glyoxamides moiety possess

potential drug activity. Looking to the diversified biological activities we have

synthesized some glyoxamides derivatives in order to achieving better therapeutic agents.

These studies are described in following section.

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 3-[N,N-

DIALKYLAMINE(OXO)ACETYL]-1-PROPYL-1H-INDOLE-2-

CARBOXYLIC ACIDS.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF 3-[N,N-

DIALKYLAMINE(OXO)ACETYL]-1-PROPYL-1H-INDOLE-2-CARBOXYLIC

ACIDS.

Heterocyclic compounds bearing Indole-3-yl-glyoxylamide ring system are

endowed with variety of biological activities. Our strategy is based on to develop a new

bioactive entity especially with pharmacological activities bearing heterocyclic ring

system. In view of our ongoing interest in the synthesis of some new Indole-3-yl-

glyoxylamide derivatives, we have under taken the condensation of 1-propyl-1H-indole-

2-carboxylic acid with oxalyl chloride and different secondary amine in the presence of

DCM.

REACTION SCHEME

NH

O

OH N

O

OH

CH3

N

O

OH

CH3

O

R

O

DMFN-Propylbromide

K2CO3 MDC, TEA(ii) Sec. amine

(i) (COCl)2


using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported

by mass spectroscopy. Purity of all the compounds has been checked on thin layer

chromatographic plate and HPLC technique.

All the synthesized compounds were tested for their antibacterial and antifungal

activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two

Gram-negative bacteria and three fungal strains. The biological activities of the

synthesized compounds have been compared with standard drugs.



EXPERIMENTAL SECTION

Melting points were determined in open capillary tubes and are uncorrected.

Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm

thickness and spots were located by iodine and UV light. IR spectra were recorded on

Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded

on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR

and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.

Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental

analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental

analyzer and the results are in agreements with the structures assigned.

[A] Preparation of 1-Propyl-1H-indole-2-carboxylic acid.

To a stirred suspension of K2CO3 (2.72 g, 0.02 mol) and 1H-indole-2-carboxylic

acid (1.61 g, 0.01 mol) in dry DMF (10 ml), 1-bromopropane (1.18 ml, 0.013 mol) was

added dropwise after 5 minute. The resultant solution was stirred for 5 hour at room

temperature, and then poured onto crushed ice, the product was isolated and washed with

water and hexane to give pure product. Yield: 93 %, mp 80-83 oC.

[B] General procedure for the preparation of 3-[N,N-Dialkylamine(oxo)acetyl]-1-

propyl-1H-indole-2-carboxylic acids.

To a stirred cooled (ice bath) solution of 1-propyl-1H-indole-2-carboxylic acid

(2.03 g, 0.01 mol) in dry DCM (15 ml), oxalyl chloride (1.27 ml, 0.015 mol) was added

dropwise in solution. The obtained solution was stirred at 0-5 oC for 10-15 minute then

add TEA (1.68 ml, 0.012 mol) dropwise. The resulting solution was stirred at 0-5 oC for

30.0 minute and then at 25-30 oC for 1 hour. Dark yellow colored was formed. The

solvent was removed in vacuo, the residue was dissolved in dry DCM (12 ml) and

different secondary amine (0.012 mol) dropwise. The reaction mixture was stirred at 0-

5 oC for 30.0 minute and then 25-30 oC for another 30.0 minute (monitored by TLC). The

solvent was removed in vacuo. The product was dissolved in water and extracted with

ethylacetate (25 ml × 3). The combined organic layers were washed with water followed

by brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the

solid was triturated with hexane and resulting precipitate was filtered, washed with

hexane and dried to give analytical pure product. The physical constants of the product

are recorder in Table-1a.



Table-1a: Physical constant of 3-[N,N-Dialkylamino(oxo)acetyl]-1-propyl-1H-indole-

2-carboxylic acids.

N

O

OH

O

R

O

CH3

Sr. No. Substitution R M. F. M. W. Yield (%) Rf value

1a N O

C18H20N2O5

344.36 83 0.46

1b NCH3

CH3 C18H22N2O4 330.37 80 0.51

1c N N

C24H25N3O4 419.47 79 0.64

1d N

C19H22N2O4

342.38 89 0.38

1e N N CH3

C19H23N3O4

357.40 85 0.47

1f N NCH3

C20H25N3O4

371.43 76 0.39

1g NCH3

CH3

CH3

CH3

C20H26N2O4

358.43 80 0.53

1h N

C18H20N2O4

328.36 82 0.51

1i N

CH3

C20H24N2O4 356.41 84 0.48

1j N CH3

C20H24N2O4

356.41 78 0.60

TLC solvent system:- E.A. : Hexane = 6 : 4



ANALYTICAL DATA

3-[Morpholin-4-yl(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1a). mp 168-

170 °C; Purity by HPLC: 94 %; IR (KBr): 3446 (O-H, str), 3023 (Ar, C-H str), 2947 (C-H

str), 2805 (C-H str), 1706 (acid, C=O str), 1633 (amide, C=O str), 1528 (Ar, C=C str),

1440 (Ar, C=C str), 1256 (C-H ban), 1152 (C-O str) cm-1; 1H NMR (400 MHz, CDCl3): δ

ppm 0.92-0.96 (t, J=7.32 Hz, 3H, CH3), 1.07-1.25 (m, 2H, CH2), 1.63-1.75 (m, 4H,

2CH2), 3.62-3.66 (t, J=7.08 Hz, 2H, CH2), 3.77-3.87 (m, 4H, 2CH2), 7.30-7.45 (m, 3H,

ArH), 8.30-8.31 (d, J=7.92 Hz, 1H, ArH), 9.77 (s, 1H, OH). 13C NMR (100 MHz,

CDCl3): δ ppm 10.28, 21.81, 41.89, 46.36, 66.27, 112.36, 116.38, 123.07, 123.85,

126.41, 127.48, 129.99, 135.13, 159.00, 166.94, 187.66; MS: m/z = 344 [M]+; Anal.

Calcd for C18H20N2O5: C, 62.78; H, 5.85; N, 8.13. Found: C, 62.67; H, 5.47; N, 8.09%.

3-[(Diethylamino)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1b). mp 133-

134 °C; Purity by HPLC: 91 %; IR (KBr): 3412, 3044, 2983, 2861, 1710, 1673, 1552,

1444, 1287, 1175 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 0.86-0.89 (t, J=7.4 Hz, 3H,

CH3), 1.29-1.34 (m, 6H, 3CH3), 1.51-1.60 (m, 2H, CH2), 3.41-3.44 (t, J=7.08 Hz, 2H,

CH2), 3.55-3.61 (m, 4H, 2CH2), 7.28-7.30 (m, 1H, ArH), 7.32-7.36 (m, 1H, ArH), 7.45-

7.47 (d, J=8.2 Hz, 1H, ArH), 8.31-8.33 (d, J=8.0 Hz, 1H, ArH), 10.11 (s, 1H, OH). 13C

NMR (100 MHz, CDCl3): δ ppm 10.17, 12.50, 13.73, 21.66, 39.35, 42.72, 66.95, 112.71,

116.09, 122.99, 123.54, 125.99, 127.59, 130.06, 135.24, 158.88, 167.89, 188.32; MS: m/z

= 330 [M]+; Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.36;

H, 6.61; N, 8.37%.

3-[(4-Phenylpiperazin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1c).

mp 153-155 °C; IR (KBr): 3502, 3101, 2961, 2852, 1708, 1678, 1533, 1456, 1248, 1156

cm-1; MS: m/z = 419 [M]+; Anal. Calcd for C24H25N3O4: C, 68.72; H, 6.01; N, 10.02.

Found: C, 68.59; H, 5.89; N, 9.95%.

3-[Oxo(piperidin-1-yl)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1d). mp 189-190

°C; IR (KBr): 3432, 3513, 3033, 2988, 2857, 1700, 1689, 1578, 1482, 1252, 1162 cm-1;

MS: m/z = 343 [M+1]+; Anal. Calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found:

C, 66.53; H, 6.31; N, 8.06%.

3-[(4-Methylpiperazin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1e).

mp 128-130 °C; IR (KBr): 3501, 3055, 2971, 2868, 1711, 1693, 1561, 1483, 1291, 1158




Found: C, 63.77; H, 6.45; N, 11.70%.

3-[(4-Ethylpiperazin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1f). mp

136-138 °C; IR (KBr): 3522, 3033, 2999, 2905, 1715, 1694, 1499, 1432, 1240, 1160 cm-

1; MS: m/z = 371 [M]+; Anal. Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found:

C, 64.63; H, 6.72; N, 11.28%.

3-[(N,N-Diisopropylamino)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1g).

mp 171-172 °C; IR (KBr): 3488, 3097, 2986, 2971, 1718, 1701, 1497, 1422, 1285, 1178


Found: C, 66.97; H, 7.28; N, 7.78%.

3-[Oxo(pyrrolidin-1-yl)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1h). mp 201-

203 °C; IR (KBr): 3489, 3098, 2978, 2891, 1706, 1681, 1499, 1488, 1280, 1171 cm-1;

MS: m/z = 328 [M]+; Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C,

65.79; H, 6.09; N, 8.47%.

3-[(2-Methylpiperidin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1i).

mp 191-193 °C; IR (KBr): 3569, 3099, 2966, 2898, 1720, 1696, 1583, 1467, 1281, 1184


Found: C, 67.35; H, 6.70; N, 7.83%.

3-[(4-Methylpiperidin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1j).

mp 149-150 °C; IR (KBr): 3546, 3084, 2997, 2951, 1717, 1687, 1576, 1455, 1279, 1187


Found: C, 67.27; H, 6.73; N, 7.81%.



SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS

HPLC of compound 1a

Column : YMC C-8 (4.6 x 150 mm, 5 µm particle size)

Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60 : 40, v/v)

Flow rate : 1.0 ml/min

Minutes0 1 2 3 4 5 6 7 8

0

500

10001

.81

3 5

91

6 0

.05

2.4

64

1

03

40

43

4 9

4.5

6

2.8

69

4

35

78

9 3

.98

3.4

13

4

34

74

0

.40

4.0

43

6

05

24

0

.55

4.5

87

1

84

08

0

.17

5.0

24

4

01

0 0

.04

5.3

76

2

58

74

0

.24

7.0

61

1

37

0 0

.01

IR spectra of compound 1a

5007501000125015001750200025003000350040001/cm

30

45

60

75

90

105

%T

3491

.27

3446

.91

3345

.64

3096

.82

3023

.52

2947

.33

2805

.56

1706

.09

1633

.76

1528

.64

1440

.87

1386

.86

1300

.07

1256

.67

1207

.48

1152

.51

1104

.28

992.

4193

8.40

817.

8577

5.41

695.

3662

6.89

537.

1951

3.08

Reaction-90 p1

N

O

OH

OO

CH3

N

O



Mass spectrum of compound 1a

Mass spectrum of compound 1c

N

O

OH

OO

CH3

N

O

M.Wt. = 344.36

N

O

OH

OO

CH3

N

N

M.Wt. = 419.47



1H NMR spectrum of compound 1a

Expanded spectrum of compound 1a

N

O

OH

OO

CH3

N

O



1H NMR spectrum of compound 1b

Expanded spectrum of compound 1b

N

O

OH

OO

CH3

N

CH3 CH3



13C NMR spectrum of compound 1a

13C NMR spectrum of compound 1b

N

O

OH

OO

CH3

N

O

N

O

OH

OO

CH3

N

CH3 CH3



ANTIMICROBIAL ACTIVITY

Biological evaluation of 3-[N,N-Dialkylamine(oxo)acetyl]-1-propyl-1H-indole-2-

carboxylic acids.

All of the synthesized compounds (1a-j) were tested for their antibacterial and

antifungal activity (MIC) in vitro by broth dilution method38-40 with two Gram-positive

bacteria Staphylococcus aureus MTCC-96 and Streptococcus pyogenes MTCC 442, two

Gram-negative bacteria Escherichia coli MTCC 443 and Pseudomonas aeruginosa

MTCC 1688 and three fungal strains Candida albicans MTCC 227, Aspergillus Niger

MTCC 282 and Aspergillus clavatus MTCC 1323 taking gentamycin, ampicillin,

chloramphenicol, ciprofloxacin, norfloxacin, nystatin and greseofulvin as standard drugs.

The standard strains were procured from the Microbial Type Culture Collection (MTCC),

Institute of Microbial Technology, Chandigarh, India.

The minimal inhibitory concentration (MIC) values for all the newly synthesized

compounds, defined as the lowest concentration of the compound preventing the visible

growth, were determined by using micro dilution broth method according to NCCLS

standards.38

Minimal Inhibition Concentration [MIC]

The main advantage of the Broth Dilution Method for MIC determination lies in

the fact that it can readily be converted to determine the MIC as well. 1. Serial dilutions were prepared in primary and secondary screening.

2. The control tube containing no antibiotic is immediately subcultured (before

inoculation) by spreading a loopful evenly over a quarter of plate of medium

suitable for the growth of the test organism and put for incubation at 37 0C

overnight.

3. The MIC of the control organism is read to check the accuracy of the drug

concentrations.

4. The lowest concentration inhibiting growth of the organism is recorded as the

MIC.

5. The amount of growth from the control tube before incubation (which represents

the original inoculums) is compared.



Methods used for primary and secondary screening

Each synthesized compounds was diluted obtaining 2000 μg mL-1 concentration,

as a stock solution. Inoculum size for test strain was adjusted to 108 cfu (colony forming

unit) per milliliter by comparing the turbidity.

Primary screen: In primary screening 1000 μg mL-1, 500 μg mL-1 and 250 μg mL-

1 concentrations of the synthesized compounds were taken. The active synthesized drugs

found in this primary screening were further tested in a second set of dilution against all

microorganisms.

Secondary screen: The compounds found active in primary screening were similarly

diluted to obtain 200 μg mL-1, 100 μg mL-1, 50 μg mL-1, 25 μg mL-1, 12.5 μg mL-1, and

6.250 μg mL-1 concentrations.

Reading Result: The highest dilution showing at least 99 % inhibition zone is taken as

MIC. The result of this is much affected by the size of the inoculums. The test mixture

should contain 108 organism/mL.

The results obtained from antimicrobial susceptibility testing are depicted in

Table 1b.



Table-1b: Antimicrobial activity of 3-[N,N-Dialkylamino(oxo)acetyl]-1-propyl-1H-

indole-2-carboxylic acids.

Sr. No.

Antibacterial Activity Antifungal activity

Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria

S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus

1a 250 250 500 500 1000 1000 1000 1b 250 100 250 500 200 500 500 1c 62.5 100 500 500 >1000 250 250 1d 100 500 250 250 250 500 200 1e 100 250 100 250 500 250 250 1f 500 200 200 100 1000 250 500 1g 200 100 62.5 100 500 500 250 1h 50 100 100 200 500 250 1000 1i 250 500 200 500 250 200 1000 1j 100 500 100 200 250 500 500

MINIMAL INHIBITION CONCENTRATION

Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa

(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100

Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10

MINIMAL FUNGICIDAL CONCENTRATION

Standard Drugs C.Albicans A.Niger A.Clavatus

(microgramme/ml) Nystatin 100 100 100

Greseofulvin 500 100 100



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Part – A

(Part – II)

Studies on Imidazolone Derivatives


Imidazolones derivatives… 48

INTRODUCTION

Imidazolinone, a five membered heterocycle having 2-nitrogen atoms at the 1 and

3-positions and C=O group at following positions: 2-oxo-imidazoline (1), 4-oxo-

imidazoline (2), 5-oxo-imidazoline (3). Imidazolines are structurally related to guanidines

and amidines.

Imidazolinone has been used extensively as a corrosion inhibitor of certain

transition metals, such as copper. Preventing copper corrosion is important, especially in

aqueous systems, where the conductivity of the copper decreases due to corrosion.

NH

NH

O NH

NHO

NH

NH

O

(1) (2) (3)

The discovery of the 2-substituted-5-imidazolines dates back to the year 1888,

when A. W. Hoffmann1 for the first time discovered 5-oxo-imidazoline by heating N1-

diacetyl ethylene diamine in a stream of dry hydrogen chloride and moreover the same

compound was prepared by A. Ladenburg2 by the fusion of two equivalents of sodium

acetate with one equivalent of ethylene diamine dihydrochloride.

SYNTHETIC ASPECT

Various methods have been reported for the synthesis of imidazolinones in

literature.3 Aminolysis of oxazolone with amines led to the formation of imidazolinones

which has been reported in literature.4

1. Saxena et al.5 have synthesized new imidazolinone derivatives (4) by the reaction

of hydrazide with azalactone in dry pyridine.

N

O

Ar

O O

NHNH2Cl

dry pyridineN

N NH

OAr O

Cl

(4) 2. X. Huang et al.6 have synthesized some new imidazolinone derivatives (5) by the

reaction of halide with acetonitrile in presence of K2CO3.



Cl

COOEt

N=C=S

R1NH2

CH3CN

Cl

NHN

O

R1

S

R2X,CH3CN

K2CO3

Cl

NN

O

SR2

R1

R1=n-Pr,R2=Aryl (5) 3. A. V. Patel et al.7 have synthesized new Imidazolinone derivatives by

conventional method.

4. Z. Han et al.8 have synthesized 5-imidazolinone derivatives with 2-bromo- acetic

acid as a starting material.

REACTION MECHANISM

Azalactone reacts with variety of compounds such as water, alcohols, amines and

hydrogen halides. Amides of α-acylamino acrylic acids obtained from the condensation of

azalactone and primary amine can be converted to imidazolinone as shown under.

N O

OR

X XO

NH NH

OR

R'R'-NH2 POCl3 N N

R

X

R'

R' = NH2, Dry C5H5N/Abs.C2H5OH, K2CO3

The ring closer can be affected under a variety of conditions. Substituted anilides

have been converted to imidazolinone derivatives by the action of POCl3.


Naphazoline hydrochloride, xylometazoline hydrochloride etc. are various

imidazolinone derivatives which have been used as adrenergic stimulants and tolazoline

and phentolamine as adrenergic blocking agents. Various imidazolinones are known to

exhibit a broad spectrum of biological activities such as:

1. Antitubercular9

2. Anti cancer10



3. Insecticidal11

4. Antiviral12

5. Hypertensive13

6. Antiinflammatory14

7. Glucagon antagonists15

8. Antimicrobial16

9. Antihistaminic17

10. Antidiabetic18

P. Sah and coworkers19 have prepared some new imidazolinones and reported

their antimicrobial and antileishmanial activities. K. M. Khan et al.20 have reported

antibacterial and fungicidal activity of 5-oxo-imidazolines. Herbicidal activity of

imidazolinone derivatives have been reported by Wang Ying et al.21 Y. Zhou et al.22 and

A. Pai et al.23 have reported anticancer active analogues of 5-oxo-imidazolines.

Imidazolinone derivatives which possess antifungal activity have been reported by M. D.

Shah et al.24 Some new 5-oxoimidazolines as antimicrobial agents have been

investigated P. S. Patel et al.25 V. Leroy and coworkers26 have prepared substituted

imidazolone derivatives and reported their pharmaceutical use as inhibitors of protein

kinases, particularly CDC7 and antiproliferative agents. N. Xue et al.27 have synthesized

and evaluated imidazol-2-one derivatives (6) as potential antitumor agents.

H3CO

H3CO

H3CO

NN CH3

OO

(6) Work done from our laboratory

A. M. Vyas28 have synthesized 1-aryl-2-methyl-4-(8-hydroxyquinolin-7-yl

methine)-5-imidazolones. Synthesis of some new imidazolones and 1,2,4-triazoles

bearing benzo[b]thiophene nucleus as antimicrobial agents have been reported by K. M.

Thakar.29 1-N-substituted benzalaminothiocarbonyl-2-methyl-4-(8'-hydroxyquinolin-7'-

yl)methine-5-imidazolones have been reported by A. M. Vyas.30



Literature survey reveals that the compounds bearing imidazolones moiety

possess potential drug activity. Looking to the diversified biological activities we have

synthesized some imidazolinone derivatives in order to achieving better therapeutic

agents. These studies are described in following section.

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF N-[(4Z)-4-

ARYLIDENE-5-OXO-2-PHENYL-4,5-DIHYDRO-1H-IMIDAZOL-1

-YL]-1H-INDOLE-2-CARBOXAMIDES.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF N-[(4Z)-4-ARYLIDENE-5-

OXO-2-PHENYL-4,5-DIHYDRO-1H-IMIDAZOL-1-YL]-1H-INDOLE-2-

CARBOXAMIDES.

Various imidazolinone have resulted in many potential drugs and are known to

possess a broad biological spectrum. In view of getting better therapeutic agents and

considering the association of various biological activities with Indole-2-carbohydrazide

nucleus, the preparation of imidazolone have been undertaken by the condensation of 1H-

indole-2-carbohydrazide with substituted azalactones which in turn have been prepared by

well known Ertenmeyer azalactone synthesis.

REACTION SCHEME

NH

O

OH NH

O

O CH3 NH

O

NH NH2

ON

H5C6

R O

Pyridine

MeOH

Con. H2SO4

MeOHHydrazine Hydrate

NH

N

O

NN

OR

H
















on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.



analyzer and the results are in agreements with the structures assigned. [A] Synthesis of 1H-Indole-2-carbohydrazide.31

Methyl 1H-indole-2-carboxylate (1.75 g, 0.01 mol) in absolute ethanol (25 ml)

was refluxed with 1.0 ml of hydrazine hydrate for 2 hour. After the completion of the

reaction checked by TLC, the reaction mixture was cooled to room temperature. The

separated solid was filtered, washed with cold ethanol and recrystallized from ethanol.

Yield 98%, m.p 247-248 °C. [B] Synthesis of 4-Arylidene-2-phenyl-5-oxazolinones.

These were prepared by the condensation of substituted benzaldehyde with

benzoyl glycine in presence of sodium acetate and acetic anhydride as described by

Vogel.32

[C] General procedure for the preparation of N-[(4Z)-4-Arylidene-5-oxo-2-

phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-indole-2-carboxamides.

To a mixture of 1H-indole-2-carbohydrazide (1.75 g, 0.01 mol) and different 4-

arylidene-2-phenyl-5-oxazolinones (0.01 mol) in a pyridine (15 ml) was refluxed for 8-10

hour (monitoring by TLC). The excess of solvent was removed under reduced pressure

and reaction mixture was poured on crushed ice. The product was isolated and

crystallized from methanol to give analytical pure product. The physical constants of the

product are recorded in Table-2a.

[D] Biological evaluation of N-[(4Z)-4-Arylidene-5-oxo-2-phenyl-4,5-dihydro-1H-


Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,

antimicrobial activity. The MIC values of the test compounds are recorded in Table-2b.



Table-2a: Physical constant of N-[(4Z)-4-Arylidene-5-oxo-2-phenyl-4,5-dihydro-1H-


NH

N

O

NN

RO

H

Sr. No Substitution R M. F. M. W. Yield (%) Rf value

2a

O CH3

C26H20N4O3 436.36 73 0.39

2b N+

O-

OC25H17N5O4 451.43 68 0.43

2c CH3 C26H20N4O2 420.46 74 0.53

2d

C25H18N4O2 406.43 78 0.36

2e Cl

C25H17ClN4O2 440.88 71 0.47

2f N

+O-

O

C25H17N5O4 451.43 70 0.62

2g OH C25H18N4O3 422.43 68 0.66

2h F

C25H17FN4O2 424.42 65 0.38

2i OCH3

C26H20N4O3 436.46 81 0.48

2j

O

O

CH3

CH3

C27H22N4O4 466.48 76 0.44




ANALYTICAL DATA

N-[(4Z)-4-(2-Methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-

1H-indole-2-carboxamide (2a). mp 236-238 °C; Purity by HPLC: 99 %; IR (KBr): 3338

(N-H str), 3059 (Ar, C-H str), 2926 (C-H str), 2847 (C-H str), 1647 (amide, C=O str),

1591 (C=N str), 1570 (Ar, C=C str), 1508 (Ar, C=C str), 1271 (C-H ban), 1026 (C-N str),

810 (C-H, o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 3.92 (s, 3H, OCH3), 6.84-

6.98 (m, 2H, ArH), 6.99-7.09 (m, 2H, ArH), 7.14-7.21 (m, 3H, ArH), 7.39-7.50 (m, 3H,

ArH), 7.52-7.60 (m, 1H, ArH), 7.74-7.79 (m, 1H, ArH), 7.98 (s, 1H, C=CH), 8.05-8.07

(d, J=7.12 Hz, 2H, ArH), 8.54 (s, 1H, NH), 10.75 (s, 1H, NH). 13C NMR (100 MHz,

CDCl3): δ ppm 55.66, 115.20, 124.06, 124.21, 124.42, 126.10, 127.20, 127.29, 127.95,

128.10, 128.95, 129.27, 129.40, 129.99, 130.08, 130.74, 137.27, 141.20, 157.35, 159.57,

189.06; MS: m/z = 437 [M+1]+; Anal. Calcd for C26H20N4O3: C, 71.55; H, 4.62; N, 12.84.

Found: C, 71.29; H, 4.47; N, 12.61%.

N-[(4Z)-4-(4-Nitrobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-

indole-2-carboxamide (2b). mp 213-215 °C; Purity by HPLC: 96 %; IR (KBr): 3443,

3068, 1697, 1591, 1522, 1445, 1260, 1040, 820 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm

7.42-7.52 (m, 3H, ArH), 7.54-7.63 (m, 3H, ArH), 7.65-7.75 (m, 1H, ArH), 7.84-7.85 (d,

J=7.08 Hz, 1H, ArH), 8.09-8.13 (m, 2H, ArH), 8.24-8.27 (d, J=11.84 Hz, 2H, ArH), 8.35

(s, 1H, C=CH), 8.52 (s, 1H, NH), 8.78-8.86 (m, 2H, ArH), 10.73 (s, 1H, NH). 13C NMR

(100 MHz, CDCl3): δ ppm 115.72, 127.60, 127.80, 128.00, 129.74, 130.20, 130.41,

130.65, 131.02, 131.72, 132.10, 132.40, 133.27, 133.62, 134.10, 137.60, 141.10, 157.48,

160.12, 191.16; MS: m/z = 451 [M]+; Anal. Calcd for C25H17N5O4: C, 66.51; H, 3.80; N,

15.51. Found: C, 66.25; H, 3.76; N, 15.42%.

N-[(4Z)-4-(4-Methylbenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-

indole-2-carboxamide (2c). mp 179-180 °C; IR (KBr): 3466, 3075, 1681, 1613, 1499,

1402, 1261, 1025, 840 cm-1; MS: m/z = 420 [M]+; Anal. Calcd for C26H20N4O2: C, 74.27;

H, 4.79; N, 13.33. Found: C, 73.95; H, 4.70; N, 13.21%.

N-[(4Z)-4-Benzylidene-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-indole-2-

carboxamide (2d). mp 163-165 °C; IR (KBr): 3469, 3076, 1706, 1646, 1576, 1466,

1281, 1021, 746 cm-1; MS: m/z = 406 [M]+; Anal. Calcd for C25H18N4O2: C, 73.88; H,

4.46; N, 13.78. Found: C, 73.58; H, 4.40; N, 13.67%.



N-[(4Z)-4-(4-Chlorobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-

indole-2-carboxamide (2e). mp 225-224 °C; IR (KBr): 3459, 3077, 1694, 1634, 1597,

1464, 1261, 1013, 866 cm-1; MS: m/z = 440 [M]+; Anal. Calcd for C25H17ClN4O2: C,

68.11; H, 3.89; N, 12.71. Found: C, 67.82; H, 3.81; N, 12.54%.

N-[(4Z)-4-(3-Nitrobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-

indole-2-carboxamide (2f). mp 183-184 °C; IR (KBr): 3492, 3064, 1705, 1625, 1599,

1406, 1242, 1039, 723 cm-1; MS: m/z = 452 [M+1]+; Anal. Calcd for C25H17N5O4: C,

66.51; H, 3.80; N, 15.51. Found: C, 66.18; H, 3.75; N, 15.39%.

N-[(4Z)-4-(4-Hydroxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-

1H-indole-2-carboxamide (2g). mp 151-153 °C; IR (KBr): 3469, 3003, 1691, 1589,

1565, 1482, 1250, 1044, 716 cm-1; MS: m/z = 422 [M]+; Anal. Calcd for C25H18N4O3: C,

71.08; H, 4.29; N, 13.26. Found: C, 70.84; H, 4.18; N, 13.08%.

N-[(4Z)-4-(4-Fluorobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-

indole-2-carboxamide (2h). mp 138-139 °C; IR (KBr): 3454, 3086, 1712, 1602, 1546,

1445, 1016, 747 cm-1; MS: m/z = 425 [M+1]+; Anal. Calcd for C25H17FN4O2: C, 70.75; H,

4.04; N, 13.20. Found: C, 70.21; H, 3.98; N, 13.07%.

N-[(4Z)-4-(4-Methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-

1H-indole-2-carboxamide (2i). mp 173-174 °C; IR (KBr): 3394, 3074, 1688, 1592,

1572, 1465, 1028, 727 cm-1; MS: m/z = 436 [M]+; Anal. Calcd for C26H20N4O3: C, 71.55;

H, 4.62; N, 12.84. Found: C, 71.16; H, 4.51; N, 12.63%.

N-[(4Z)-4-(2,5-Dimethoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-

yl]-1H-indole-2-carboxamide (2j). mp 201-202 °C; IR (KBr): 3386, 3056, 1690, 1587,

1585, 1464, 1024, 723 cm-1; MS: m/z = 467 [M+1]+; Anal. Calcd for C27H22N4O4: C,

69.52; H, 4.75; N, 12.01. Found: C, 69.27; H, 4.63; N, 11.94%.




HPLC of compound 2a


Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60: 40, v/v).



Minutes0 1 2 3 4 5 6 7 8 9 10

mA

U

0

250

500

750

1.46

1 1

484

0.0

21.

664

197

0.0

01.

909

347

4 0

.05

2.53

9 2

378

0.0

3

2.95

5 1

063

0.0

13.

200

263

0.0

03.

381

199

0.0

03.

701

598

6 0

.08

4.39

5 7

3548

94 9

9.72

5.08

8 1

145

0.0

2

5.95

2 3

56 0

.00

6.49

6 2

382

0.0

3

7.77

6 1

616

0.0

2

5007501000125015001750200025003000350040001/cm

20

40

60

80

100

%T

3543

.35

3392

.90

3338

.89 32

38.5

930

59.2

029

26.1

128

47.0

3

1647

.26

1591

.33

1570

.11

1548

.89

1508

.38

1406

.15

1340

.57

1271

.13

1224

.84

1168

.90

1026

.16

837.

1381

0.13 55

7.45

507.

3044

7.50

KAJ-CHAL-OME

NH

N

O

NN

OO

CH3

H





NH

N

O

NN

OO

CH3

H

M. Wt. = 436.46

NH

N

O

NN

O

H CH3

M. Wt. = 420.46





NH

N

O

NN

OO

CH3

H





NH

N

O

NN

O

HN

+

O-

O





NH

N

O

NN

OO

CH3

H

NH

N

O

NN

O

HN

+

O-

O



Table-2b: Antimicrobial activity of N-[(4Z)-4-Arylidene-5-oxo-2-phenyl-4,5-dihydro-

1H-imidazol-1-yl]-1H-indole-2-carboxamides.

Sr. No.




2a 100 50 62.5 100 200 500 250 2b 200 200 100 250 500 200 500 2c 100 100 250 250 500 1000 1000 2d 500 250 500 100 250 250 500 2e 500 500 100 100 500 1000 1000 2f 250 500 100 500 1000 250 500 2g 250 100 200 200 >1000 200 250 2h 200 250 100 500 500 1000 250 2i 500 500 500 250 500 500 500 2j 200 500 250 250 250 500 200











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McCormick, J. J. Piwinski, R. E. West, J. C. Anthes, S. M. Williams, W. Ren-Long, S. H.

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Part – A

(Part – III)

Studies on Oxadiazole Derivatives


Oxadiazole derivatives… 65

INTRODUCTION

Oxadiazoles belong to an important group of heterocyclic compounds

having –N=C-O- linkage. It is well documented that oxadiazole system contains

the following members which are numbered by designating the hetero atoms at

particular position.

NN

ON

O

NN

ON

N

O

N

(1) (2) (3) (4)

1,3,4-Oxadiazole is a heterocyclic molecule with oxygen atom at 1 and two

nitrogen atoms at 3 and 4 position. 1,3,4-Oxadiazole is a thermally stable aromatic

molecule.1 They have been known for about 80 years it is only in the last decade

that investigations in this field have been intensified. This is because of large number

of applications of 1,3,4-oxadiazoles in the most diverse areas viz. drug

synthesis, dye stuff industry, heat resistant materials, heat resistant polymers and

scintillators. Reviews of the relevant literature prior to 1965 are available.2

SYNTHETIC ASPECT

Most 1,3,4-oxadiazoles are best obtained by synthesis from acyclic precursors.

Such reactions are ‘one bond’ or ‘two bond’ cyclization. Different methods for the

synthesis have been cited in literature.3-8 1. B. Chandrakantha et al.9 have synthesized oxadiazoles (5) by the reaction of

hydrazide and aromatic acid in presence of POCl3.

O

NH

ONH2

F

O

F N

O

NRPOCl3 + R-COOH

110 oC

(5)

2. D. Ramesh and B. Sreenivasan10 have synthesized 1,3,4-oxadiazoles (6) from

semicarbazide in presense of POCl3.



N N

NH O

NHNH

O

POCl3Ref. 4 h. N N

NH N

ON

R(6)

3. K. Mogilaiah and B. Sakram11 have prepared 1,3,4-oxadiazoles (7) from

acetophenone-2-trifluoromethyl-1,8-naphthyridine-3-carbonyl hydrazone in

presence of acetic anhydride.

N N

NH

O

CF3

N

Ar

AC2O

N N CF3

N

O

N

O

Ar

(7) 4. Yu Yuve have reported microwave-assisted synthesis protocol of oxadiazoles (8)

with 91 % of the yield.12

R NH

ONH2

R1

O

OH O

N N

R R1

(8)

POCl3MW, 12 min

+

5. L. Somogyi13 synthesized 1,3,4-oxadiazoles (9) from several steps, from aryl

hydrazides and aryl aldehydes.

RNH

O

NH2

R1

OAc Cl

O

N N

R R1

(9)

+ +

6. Silica sulfuric acid catalyst used for the rapid and ecofriendly synthesis of 1,3,4-

oxadiazoles (10) at ambient temperature reported by M. Dabiri et al.14

R C(OEt)3 R1

NH

O

NH2O

N N

R R1

Silica, H 2SO4

MW,10min

(10)

+

7. Green chemistry and one-pot, solvent-free using microwave mediated synthesis of



1,3,4-oxadiazoles (11) were reported by V. Polshettiwar.15

R C(OEt)3 R1

NH

O

NH2 O

N N

R R1

(11)

MW80

oC, 10 min

+

REACTION MECHANISM

N

CH3

O

NH NH2

Cl CR

O+

..

N

CH3

O

NH N+H

C

H

O-

R

Cl

N

CH3

O

NH N+H

C

H

OR-Cl

N

CH3

O

NH N

H

CO

R

-H+

N

CH3

O+

N N

H

C

O-

R

H

N

CH3

N+

O

N

HH

O-

R

N

CH3

N

O

NH

OH

R N

CH3

N

O

N

R-H 2O


2,5-Disubstituted-1,3,4-oxadiazole derivatives have been tested for various

pharmacological activities, which have been summarized as under.

1. Antibacterial16


3. Analgesic18

4. Antiviral and anticancer19

5. Antihypertensive20

6. Anticonvulsant21

7. Antiproliferative22

8. Antifungal23

9. Cardiovascular24



10. Herbicidal25

11. Hypoglycemic26

12. Hypnotic and Sedative27

13. MAO inhibitor28

14. Insecticidal29

S. R. Bishnoi et al.30 have screened oxadiazoles for their antimicrobial activity.

A. El-Azzouny et al.31 have synthesized 1,3,4-oxadiazole derivatives and evaluated for

their analgesic, anti-inflammatory, ulcerogenic effects and inhibitory activity on

plasma prostaglandin E2 (PGE2) Level.

S. V. Bhandari et al.32 have reported 1,3,4-oxadiazoles for their anti-

inflammatory activity. Song Cao et al.33 have investigated some oxadiazoles possessing

insecticidal activity. G. V. Suresh Kumar et al.34 have discovered oxadiazole derivatives

and reported their antimycobacterial activity. Ali Almasired et al.35 have prepared 1,3,4-

oxadiazoles of type (12) as anticonvulsant agent. Meria Grazia Mamolo et al.36 have

synthesized 3-substituted-5-(pyridine-4-yl)-3H-1,3,4-oxadiazole-2-ones of type (13)

and studied their antimycobacterial activity.

O

N N

ONH2

F

(12)

NO

N NX

O

(13)

Krishna Kant Jha et al.37 have reported antimicrobial activity of oxadiazole

derivatives. J. A. Christopher et al.38 have documented human immunodeficiency virus

(HIV) infection of 1,3,4-oxadiazole derivatives. S. J. Gilani et al.39 have synthesized

some oxadiazoles as anti-inflammatory and analgesic agents. K. Subrahmanya Bhat et

al.40 have prepared new fluorine containing 1,3,4-oxadiazoles (14) and reported them as

potential antibacterial and anticancer agents. T. P. Mohan et al.41 have synthesized

2,5-disubstituted-1,3,4-oxadiazole derivatives (15) and screened for their insecticidal

activity.



(14)

O

CH3 CH2O

N N

R

(15)

N

O

N

ClCl

F R

Ronald Kim et al.42 have discovered oxadiazole derivatives useful as protease

inhibitors. Mohd Amir and Kumar Shikha43 have documented anti-inflammatory,

analgesic and ulcerogenic activity of some newly synthesized oxadiazoles. A. Ali et

al.44 have investigated some oxadiazole derivatives possessing antimicrobial and

anti-HIV-1 activity. A. Sherif et al.45 have reported oxadiazoles as potential

antitumor and anti-HIV agents. A. Zarghi et al.46 have synthesized R-substituted-5-

(2-benzyloxyphenyl)-1,3,4-oxadiazoles (16) possessing anticonvulsant activity. M.

Tareq et al.47 have synthesized 2,5-disubstituted-1,3,4-oxadiazoles (17) useful as

tyrosinase inhibitors.

N

O

NNH2

O

F(16)

N

O

NBr

N(17)

Work done from our laboratory

K. M. Thaker48 have synthesized 2-(3',5'-dichlorobenzo[b]thiophen-2'-yl)-5-

aryl-1,3,4-oxadiazoles in the presence of aromatic acid. S. L. Vasoya49 reported facile

synthesis of some new acetyl oxadiazoles bearing benzo[b]thiophene nucleus as a

potent biological active agent. Preparation and antimicrobial activity of 2-aryl-5-(5',7'-

diiodo-8'-quinolinoxy)-1,3,4-oxadiazoles have been reported by H. S. Joshi.50 Thus

with an effort to capitalize the biological potential of the heterocyclic system and to

provide more interesting compounds for biological screening, we have under taken the

synthesis of several oxadiazoles which has been described as under.

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(5-ARYL-

1,3,4-OXADIAZOL-2-YL)-1-PROPYL-1H-INDOLES.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(5-ARYL-1,3,4-

OXADIAZOL-2-YL)-1-PROPYL-1H-INDOLES.

Synthesis of 1,3,4-oxadiazole derivatives has attracted considerable attention

in view of therapeutic applications. Looking to this, the synthesis of 1,3,4-

oxadiazoles was undertaken by the condensation of different aromatic acid with 1-

propyl-1H-indole-2-carbohydrazide in presence of phosphorous oxychloride, as

show in reaction scheme.

REACTION SCHEME

N

CH3

O

OH N

O

O CH3

CH3

N

O

NH NH2

CH3

MeOHHydrazine Hydrate

MeOH

Con. H2SO4

R-COOHPOCl3

N

CH3

N

O

N

R




















[A] Synthesis of 1-Propyl-1H-indole-2-carbohydrazide.

Methyl 1-propyl-1H-indole-2-carboxylate (2.17 g, 0.01 mol) in absolute ethanol

(25 ml) was refluxed with hydrazine hydrate (1.0 ml) for 2 hour. After the completion of

the reaction checked by TLC, the reaction mixture was cooled to room temperature. The

separated solid was filtered, washed with cold ethanol and crystallized from ethanol.

[B] General procedure for the preparation of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-

propyl-1H-indole.

A mixture of 1-propyl-1H-indole-2-carbohydrazide (2.17 g, 0.01 mol) and

different aryl acids (0.01 mol) in phosphorous oxychloride (10 ml), was refluxed with

continuous stirring. After completion the reaction (8-10 hour monitoring by TLC), the

content was cooled to room temperature then add ice cooled water and neutralized with

sodium bicarbonate solution. Then extracted into ethyl acetate. The organic extracts was

washed with water (2 x 10 ml), dried with Na2SO4, solvent was removed in vacuo and the

resulting crude product was purified by colum chromatography to give the analytical pure

compound. The physical constants of the product are recorded in Table-3a.

[C] Biological evaluation of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-propyl-1H-indole.





Table-3a: Physical constant of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-propyl-1H-indoles.

N

CH3

N

O

N

R


3a

Cl

C19H16ClN3O

337.80 83 0.42

3b N

+O

-

O C19H16N4O3

348.35 79 0.39

3c OCH3

C20H19N3O2

333.38 85 0.51

3d NH2

C19H18N4O

318.37 91 0.47

3e

Cl

C19H16ClN3O

337.80 86 0.52

3f N

+O

-

O

C19H16N4O3

348.35

76

0.56

3g F

C19H16FN3O

321.34 77 0.49

3h

Cl

N+

O-

O

C19H15ClN4O3

382.80 71 0.36

3i N

C18H16N4O

304.34 81 0.63

3j

OH

C19H17N3O2

319.35 78 0.61




ANALYTICAL DATA

2-[5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3a). mp 133-135 °C;

Purity by HPLC: 87 %; IR (KBr): 3001 (Ar, C-H str), 2933 (C-H str), 2908 (C-H str),

1626 (oxadiazole, C=N str ), 1585 (Ar, C=C str), 1533 (Ar, C=C str), 1465 (C-O-C str),

1172 (N-N str), 748 (C-H, o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 0.96-1.00

(t, J=7.44 Hz, 3H, CH3), 1.87-1.96 (m, 2H, CH2), 4.70-4.74 (t, J=7.48 Hz, 2H, CH2),


J=8.0 Hz, 1H, ArH), 8.03-8.05 (m, 1H, ArH), 8.11-8.12 (m, 1H, ArH). 13C NMR (100

MHz, CDCl3): δ ppm 11.28, 23.57, 46.75, 107.13, 110.53, 120.75, 122.09, 122.33,

124.67, 125.07, 125.33, 126.93, 126.94, 130.52, 131.84, 135.27, 139.10, 159.87, 162.44;

MS: m/z = 340 [M+2]+; Anal. Calcd for C19H16ClN3O: C, 67.56; H, 4.77; N, 12.44.

Found: C, 66.89; H, 4.68; N, 12.36%.

2-[5-(3-Nitrophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3b). mp 148-149 °C;

Purity by HPLC: 86 %; IR (KBr): 3064, 2972, 2859, 1700, 1643, 1576, 1435, 1141, 720

cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 0.97-1.00 (t, J=7.28 Hz, 3H, CH3), 1.89-1.99

(m, 2H, CH2), 4.91-4.95 (t, J=7.48 Hz, 2H, CH2), 7.33-7.37 (m, 1H, ArH), 7.50-7.54 (m,

3H, ArH), 7.62-7.63 (d, J=7.08 Hz, 1H, ArH), 7.87-7.89 (d, J=7.4 Hz, 1H, ArH), 8.20-

8.23 (m, 2H, ArH), 8.28-8.30 (m, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 11.10,

22.17, 47.10, 109.00, 112.00, 121.15, 121.50, 121.99, 126.01, 126.50, 126.94, 128.30,

128.55, 131.01, 132.31, 136.70, 140.57, 160.13, 164.17; MS: m/z = 348 [M]+; Anal.

Calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08. Found: C, 65.18; H, 4.57; N, 15.93%.

2-[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3c). mp 123-125

°C; IR (KBr): 3030, 2964, 2853, 1642, 1612, 1581, 1471, 1156, 819 cm-1; MS: m/z =

334 [M+1]+; Anal. Calcd for C20H19N3O2: C, 72.05; H, 5.74; N, 12.60. Found: C, 71.35;

H, 5.64; N, 12.55%.

4-[5-(1-Propyl-1H-indol-2-yl)-1,3,4-oxadiazol-2-yl]aniline (3d). mp 117-119 °C; IR

(KBr): 3074, 2987, 2851, 1645, 1612, 1585, 1468, 1184, 820 cm-1; MS: m/z = 318 [M]+;

Anal. Calcd for C19H18N4O: C, 71.68; H, 5.70; N, 17.60. Found: C, 71.28; H, 5.63; N,

17.54%.

2-[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3e). mp 109-111 °C;

IR (KBr): 3081, 2975, 2844, 1641, 1579, 1556, 1464, 1202, 750 cm-1; MS: m/z = 338



[M+1]+; Anal. Calcd for C19H16ClN3O: C, 67.56; H, 4.77; N, 12.44. Found: C, 67.20; H,

4.61; N, 12.33%.

2-[5-(4-Nitrophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3f). mp 178-179 °C;

IR (KBr): 3080, 2983, 2867, 1629, 1572, 1525, 1462, 1245, 1196, 830 cm-1; MS: m/z =

348 [M]+; Anal. Calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08. Found: C, 65.03; H,

4.48; N, 15.83%.

2-[5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3g). mp 165-167 °C;

IR (KBr): 3077, 2978, 2863, 1625, 1609, 1563, 1464, 1238, 1142, 870 cm-1; MS: m/z =

323 [M+2]+; Anal. Calcd for C19H16FN3O: C, 71.01; H, 5.02; N, 13.08. Found: C, 70.65;

H, 5.00; N, 12.91%.

2-[5-(2-Chloro-5-nitrophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3h). mp 139-

141 °C; IR (KBr): 2962, 2854, 1603, 1545, 1542, 1452, 1260, 1146 cm-1; MS: m/z = 383

[M+1]+; Anal. Calcd for C19H15ClN4O3: C, 59.61; H, 3.95; N, 14.64. Found: C, 59.35; H,

3.87; N, 14.54%.

1-Propyl-2-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1H-indole (3i). mp 141-143 °C; IR

(KBr): 3075, 2964, 2853, 1721, 1601, 1581, 1423, 1149, 720 cm-1; MS: m/z = 304 [M]+;

Anal. Calcd for C18H16N4O: C, 71.04; H, 5.30; N, 18.41. Found: C, 70.65; H, 5.07; N,

18.37%.

2-[5-(1-Propyl-1H-indol-2-yl)-1,3,4-oxadiazol-2-yl]phenol (3j). mp 184-186 °C; IR

(KBr): 3061, 2951, 2872, 1689, 1589, 1579, 1462, 1099, 755 cm-1; MS: m/z = 319 [M]+;

Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.08; H, 5.21; N,

13.01%.




HPLC of compound 3a

Column : Phenomenex Luna C8 (2) (250mm x 4.6mm i.d., 5 μm particle size)




Minutes0 2 4 6 8 10 12 14

mA

U

0

200

400

0.30

9 0

.01

344

2.06

9 0

.25

102

792.

325

0.4

1 1

6795

2.82

7 1

0.66

433

927

3.50

9 0

.23

941

3

4.00

0 0

.27

109

84

4.70

4 0

.11

436

7

5.48

3 0

.08

332

8

6.04

8 0

.13

515

5

6.78

4 8

7.31

355

5119

7.78

7 0

.32

129

83

8.78

9 0

.09

368

1

11.6

59 0

.01

348

5007501000125015001750200025003000350040001/cm

30

45

60

75

90

105

%T

3001

.34

2933

.83

2908

.75

2850

.88 16

87.7

716

26.0

515

85.5

415

33.4

614

65.9

5

1344

.43

1292

.35

1197

.83

1172

.76

1122

.61 10

93.6

710

49.3

110

10.7

398

7.59

902.

7282

9.42

748.

41 709.

8365

1.96

569.

0250

5.37

464.

86

JP- 504

N

CH3

N

O

N

Cl





N

CH3

N

O

N

Cl

M. Wt. = 337.80

N

CH3

N

O

N

OCH3

M. Wt. = 333.38





N

CH3

N

O

N

Cl





N

CH3

N

O

N

N+

O-

O





N

CH3

N

O

N

Cl

N

CH3

N

O

N

N+

O-

O



Table-3b: Antimicrobial activity of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-propyl-1H-

indoles.

Sr. No.




3a 500 500 200 250 1000 250 500 3b 100 200 250 62.5 500 500 1000 3c 250 250 100 200 1000 500 500 3d 50 100 500 250 200 250 200 3e 250 200 500 100 250 1000 500 3f 500 250 250 200 >1000 500 200 3g 250 100 100 500 500 250 500 3h 250 500 500 200 250 500 1000 3i 200 500 200 150 250 500 500 3j 62.5 100 100 100 200 200 250











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Part – B

Introduction

Studies on Imidazo[1,2-a]pyridine Derivatives


Imidazo[1,2-a]pyridine… 84

INTRODUCTION

Bridge nitrogen containing fused heterocycles represents important building

blocks in both natural and synthetic bioactive compounds which have been shown to

possess diverse therapeutic activities.1 Hence they are interesting target to be prepared to

our research on medicinally interesting heterocyclic entities. Aza-indolizine are of two

types, imidazo[1,2-a]pyridine (1) and imidazo[1,5-a]pyridine (2).

N

N

NN

(1) (2)

The aza-indolizine contains a phenyl ring fused to a imidazole ring is indicated in

the structure, hence it is also known as imidazo[1,2-a]pyridine.2 Several procedure for

their synthesis have been extensively studied. Such studies have been stimulated by

various promising applications, especially in the case of bridgehead nitrogen containing

fused heterocyclic entities.

The constitution of imidazo[1,2-a]pyridine was reviewed by W. L. Mosby3 in

1961. Imidazo[1,2-a]pyridine derivatives not only known for their pharmacological

applications, they are also used in disperse dyes.4

SYNTHETIC ASPECT

Classical methods have been reported in the literature for the synthesis of

imidazo[1,2-a]pyridines. The procedure for synthesizing imidazo[1,2-a]pyridines have

been described as under.

1. The synthesis of imidazo[1,2-a]pyridine from 2-aminopyridine with ω-

bromoacetophenone was reported by M. Aginagalde.5

2. 2-Acetylimidazo[1,2-a]pyridine6 can be constructed by the cyclocondensation of

2-aminopyridine with bromo butanedione.

N NH2Ph C

OCH2Br

N

NPh+



N

N

CH3

O

3. Reaction of 2-chloropyridine with 1,2,3-triazoles and subsequent elimination of

nitrogen’s give the imidazo[1,2-a]pyridine.7

NHN

NN

N

N Cl+

4. Shankarappa A Biradar8 have synthesized 6-bromo-2-(3,4-dichlorophenyl)

imidazo[1,2-a]pyridine using microwave irradiation from 5-bromo-2-

aminopyridine and 2-bromo-1-(3,4-dichlorophenyl)ethanone.

N

Br

NH2

Cl

Cl

O

Br

Microwave DMF N

N

Br

Cl

Cl+

5. Jumat Salimon et al.9 synthesized imidazo[1,2-a]pyridine-3(2H)-one and 3-

Substituted-4-yl imidazo[1,2-a] pyridine from 2-aminopyridine.

N NH2

N N

(a)

N NN N

O(c)

(b)

(i) (ii) (iii)

(i) 4-phenyl phenacyl bromide(ii) phenacyl chloride(iii) chloro aceticacid

6. Synthesis of imidazo[1,2-a]pyridines using catalytic zinc chloride microwave

irradiation from 2-aminopyridine and aryl aldehyde, aryl nitrile reported by

Amanda L. Rousseau.10



N NH2

R-CHO

R2NC

catalystN

NR

NHR2

7. Synthesis of Cu(OTf)2-catalyzed imidazo[1,2-a]pyridines from a-diazoketones

and 2-aminopyridines reported by J. S. Yadav.11

N NH2

Cu(OTf)2+O

N2Cl

CF3DCE,80'C

Cl

F3CN

N

8. Guchhait and coworkers12 reported towards molecular diversity: dealkylation of

tert-butyl amine in Ugi-type multicomponent reaction product establishes tert-

butyl isocyanide as a useful convertible isonitrile.

N

NCl

NH2

N NH2

CHO

Cl

N+

CHt-Bu+ +

9. Zhu Dongjian et al.13 have synthesized imidazo[1,2-a]pyridines from 2-

aminopyridine and phenasyl bromide at room temperature.

NNH2

PhC(=O)CH2Br 10 min, rt N

NPh+

REACTION MECHANISM

N

NH2

R4R3

R2R1

X

R5 R6

O

N+

NH2

R4R3

R2R1 R5

R6

O

X-

N

N

R4R3

R2R1

R5

R6

(3) (4) (5) (6)

+



The majority of imidazo[1,2-a]pyridine have been synthesized by the reaction of

2-aminopyridine with a a-halocarbonyl compound which form oniumhalide which is

further cyclize at room temperature to gives imidazo[1,2-a]pyridine.


Imidazo[1,2-a]pyridines are potential bioactive agents due to their wide spectrum

of therapeutic importance. A large number of substituted imidazo[1,2-a]pyridine

derivatives are prepared and tested for varieties of biological activities such as,


2. Anti cancer15

3. Antiviral16,17

4. Antianxiety18

5. Antiulcer19,20

6. Antifungal agents21

7. Antibacterials22,23

8. Hypnotic24

9. Gastric antisecretory25

10. Antimalarial26

11. Anticancer27

12. Anticytomegalo-zoster and antivaricellazoster virus28

Alexander C. Humphries and coworkers29

have synthesized 8-fluoro imidazo[1,2-

a]pyridine derivatives (7) and evaluated as a bioisosteric replacement for imidazo[1,2-

a]pyridine in an allosteric modulator ligand of the GABA-A receptor. Carlos Jaramillo,

and coworkers30 reported stereo dynamics of Ar–CO rotation and conformational

preferences of 2-amino-3-(2,4-difluorobenzoyl)-imidazo[1,2-a]pyridine. I. Aramori et

al.31 have been synthesized imidazo[1,2-a]pyridine derivatives which are highly potent

and selective non-peptide bradykinin receptor antagonist (8).



N

N

F

F

NC

OH N

N

O

NNH

O

O

N

OBr

(7) (8)

Several imidazo[1,2-a]pyridine nucleus already in market which include

alpidem32 [a ligand of both the central benzodiazepine receptors and the peripheral type

(Mitochondrial) benzodiazepine receptor] has sedative and anxiolytic properties and

zolpidem32 [a selective ligand for the central benzodiazepine receptor] is a hypnotic drug.

Both alpidem and zolpidem have higher affinity for benzodiazepine-1 than for

benzodiazepine-2 receptors33 and their interaction with various receptors has been

reported.34

N

N

ON

ClCl

CH2-CH2-CH3H3C-H2C-H2C

Alpidem

N

N

ON

CH3CH3

CH3CH3

Zolpidem

James J. Kaminski and coworkers35 have investigated imidazo[1,2-a]pyridine

derivative 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine (9) for

an antiulcer activity. On the basis of the reported metabolism of zolimidine, they reported

that the 3-cyanomethyl and 8-phenylmethoxy group have been established as metabolic

sites.

ON

N

NCH2C(9)

N

NPhSO2CH3-P

Zolmidine

Brian A. Johns et al.36 and Chaouni-Bendallah A. et al.37 synthesized a novel

imidazo[1,2-a]pyridines (10) with potent activity against Herpes Simplex viruses. J. T.



Starr et al.38 have synthesized 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridines (11) from 2-

amino-4-bromo-6-ethoxycarbonylpyridine and evaluated as a antibacterial agent.

(10)

N

N

NN

NNH

NHEtO

(11)

N

N

N

NNH

NH

F

Sebastien Follot et al.39 have synthesized 2-(4-fluorophenyl)-6-iodo-3-pyridin-4-

limidazo[1,2-a]pyridine (12) from 6-iodo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine and

evaluated as anti-apoptosis agents. Imidazo[1,2-a]pyridine units appear as important

building blocks in both natural and synthetic bioactive compounds40-42 and recognition on

DNA binding and to yield different pharmacokinetic profile.

N

N

N

IF

(12)

Mohamed A. Ismail and coworkers43 have synthesized some newer diamine

imidazo[1,2-a]pyridine (13), 5,6,7,8-tetrahydo imidazo[1,2-a]pyridines and their

corresponding N-hydroxy and N-methoxy analogues and evaluated against Trypanosoma

b. rhodesiense (T. B. rhodesiense) and Plasmodium falciparum (P. falciparum). Luke R.

Odell and coworkers44 have synthesized 6-substituted 3-amino-imidazo[1,2-a]pyridines

(14) which has active against Mycobacterium tuberculosis glutamine synthetase

inhibitors. R. B. Lacerda and coworkers45 have find out a novel analgesic and anti-

inflammatory 3-arylamine- imidazo [1,2-a] pyridine.



N

N

NH

NH2

O

NH2

NH

(13)

N

N

NHR

1

OH

O

(14) Work done from our laboratory

M. J. Ladani et al.46 reported oxopyrimidines and thiopyrimidines of 2-(2,4-

dichlorophenyl)imidazo[1,2-a]pyridin-3-carbaldehyde and their biological study.

Thus the important role displayed by imidazo[1,2-a]pyridine and its derivatives

for various therapeutic and biological activities prompted us to synthesize some

Glyoxylamide, Mannich base and Bis-Imidazo[1,2-a]Pyridin derivatives bearing

Imidazo[1,2-a]pyridine moiety in order to achieve compounds having better therapeutic

activities described as in the following parts.

STUDIES ON IMIDAZO[1,2-a]PYRIDINE DERIVATIVES


DERIVATIVES





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Therapeutics, 328(3), 1000-1006 (2009).

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12415–12419 (2006).

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Part – B

(Part – I)

Studies on Imidazo[1,2-a]pyridine-3-yl-glyoxylamide Derivatives



INTRODUCTION

Imidazo[1,2-a]pyridine-3-yl-glyoxylamide derivatives having nitrogen-bridgehead

fused heterocycles containing an imidazole ring. It is a common structural motif in

pharmacologically important molecules, with activities spanning a diverse range of

targets.1,2 The diversity, efficiency and rapid access to small and highly functionalized

organic molecules makes this approach of central current interest in the construction of

compounds library and optimization in drug discovery process.3,4

N

N

O

NO

R1

R2

In recent year glyoxylamide derivatives have gained lot of interest because of their

prominent pharmaceutical properties.

SYNTHETIC ASPECT

Various methods for the preparation of imidazo[1,2-a]pyridine-3-yl-glyoxylamide

derivatives have been cited in literature, some of the methods are as under.

1. R. Max and coworkers5 have synthesized imidazopyridinylacetamide derivatives

from imidazopyridine using oxalyl halide and amine.

N

NCH3

CH3

O

Cl O

Cl NHCH3CH3 N

NCH3

CH3

O N

O

+ +

2. T. Eszter et al.6 have synthesized primary amide and keto amide via palladium-

catalyzed carbonylation-deprotection reaction sequence.

IC CH3

NH2

CH3

CH3 CH O+

O

O

NH2+ +

3. B. Roman et al.7 reported mild and efficient conversion of nitriles to amides with

basic urea-hydrogen peroxide adduct.



CN

O O

O

NH2

4. L. K. Tin et al.8 reported catalytic hydration of nitriles to amides with manganese

dioxide on silica gel.

CNO

O

NH2


See Part-A, Part-I, Section-I, Therapeutic importance

Looking to the diversified biological activities we have synthesized some

glyoxylamide derivatives in order to achieving better therapeutic agents. These studies are

described in following section.

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-[2-(4-

FLUOROPHENYL)-6-METHYLIMIDAZO[1,2-a]PYRIDIN-3-YL]-

2-(N,N-DIALKYLAMINE-4-YL)ETHANE-1,2-DIONES.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-[2-(4-FLUOROPHENYL)-

6-METHYLIMIDAZO[1,2-a]PYRIDIN-3-YL]-2-(N,N-DIALKYLAMINE-4-YL)

ETHANE-1,2-DIONES.

The discovery of Imidazo[1,2-a]pyridine-3-yl-glyoxylamide derivatives as potent

biologically active agent has led to the exploration of large number of structural variants,

containing imidazo[1,2-a]pyridine-3-yl-glyoxylamide moiety as an invariable ingredient.

In view of these reports, we have synthesize imidazo[1,2-a]pyridine-3-yl-glyoxylamide

derivatives by the condensation of 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine

with oxalyl chloride and different secondary amine in the presence of DCM.

REACTION SCHEME

N NH2

CH3

OCl

FN

NF

CH3

N

NF

CH3OO

R

MeOHTEA

(ii) Sec. amine

(i) (COCl)2

+




















[A] Synthesis of 2-(4-Fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine.

A solution of 5-methylpyridin-2-amine (1.08 g, 0.01 mol) in methanol (10 ml)

was added to 2-chloro-1-(4-fluorophenyl)ethanone (1.72 g, 0.01 mol) and the reaction

mixture was refluxed with stirring for 6 hour in the presence of catalytic amount of TEA.

After the completion of reaction (monitoring by TLC), cool the content, the solid

separated was filtered and dried in vacuo. Yield 68%, m.p 192 °C, Anal. Calcd. for

C14H11FN2: Require: C, 74.32, H, 4.90, N, 12.38 %; Found: C, 74.30, H, 4.89, N, 12.35

%. MS: m/z = 226.

[B] General procedure for the preparation of 1-[2-(4-Fluorophenyl)-6-

methylimidazo[1,2-a]pyridin-3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-

diones.

To a stirred solution of oxalyl chloride (1.01 ml, 0.012 mol) in dry DCM (10 ml),

2-(4-Fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (2.26 g, 0.01 mol) was added

portion wise in solution. The obtained solution was stirred at room temperature for 10-15

minute and then added TEA (1.22 ml, 0.012 mol) dropwise. The resulting mixture was

stirred 25-30 oC for 2 hour dark yellow colored was formed. The solvent was removed in

vacuo, the residue was dissolved in dry DCM (12 ml) and different secondary amine

(0.015 mol) was added dropwise. The reaction mixture was stirred at 0 oC for 30.0 minute

and then 25-30 oC for another 30.0 minute (monitored by TLC). The solvent was removed

in vacuo. The product was extracted with ethyl acetate and the organic layers washed

with water, dried over anhydrous Na2SO4. The solvent was removed in vacuo and the

solid was triturated with hexane and resulting precipitate was filtered, washed with



hexane and dried to give analytical pure product. The physical constants of the product

are recorded in Table-4a.

[C] Biological evaluation of 1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]

pyridin-3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-diones.





Table-4a: Physical constant of 1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]


N

NF

CH3OO

R

Sr. No Substitution R M.F. M.W. Yield (%) Rf value

4a N O

C20H18FN3O3

367.37 86 0.49

4b NCH3

CH3

C20H20FN3O2

353.59 81 0.36

4c N N C26H23FN4O2 442.48 76 0.57

4d N

C21H20FN3O2

356.40 90 0.61

4e N N CH3

C21H21FN4O2

380.41 85 0.38

4f N NCH3

C22H23FN4O2

394.44 89 0.43

4g NCH3

CH3

CH3

CH3

C22H24FN3O2

381.44 83 0.39

4h N

C20H18FN3O2

351.37 78 0.56

4i N

CH3

C22H22FN3O2

379.42 82 0.45

4j N CH3

C22H22FN3O2

379.42 77 0.46




ANALYTICAL DATA

1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(morpholin-4-yl)

ethane-1,2-dione (4a). mp 196-198 °C; Purity by HPLC: 97 %; IR (KBr): 3116 (Ar, C-H

str), 2979 (C-H str), 2942 (C-H str), 1729 (ketone, C=O str), 1708 (amide, C=O str), 1627

(C=N str), 1528 (Ar, C=C str), 1442 (Ar, C=C str), 1254 (C-N str), 1090 (C-F) cm-1; 1H

NMR (400 MHz, CDCl3): δ ppm 2.48 (s, 3H, CH3), 3.14-3.19 (m, 4H, CH2), 3.43-3.49

(m, 4H, CH2), 7.15-7.20 (m, 2H, ArH), 7.50-7.52 (m, 1H, ArH), 7.60-7.65 (m, 2H, ArH),

7.71-7.73 (d, J=9.08 Hz, 1H, ArH), 9.57 (s, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ

ppm 18.51, 40.84, 45.90, 65.97, 114.98, 115.20, 116.79, 118.52, 126.31, 127.41, 129.06,

129.09, 132.01, 132.09, 134.07, 147.13, 156.41, 162.41, 164.46, 164.90, 180.61; MS: m/z

= 368 [M+1]+; Anal. Calcd for C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C,

64.87; H, 4.87; N, 11.32%.

N,N-Diethyl-2-[2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-

oxoacetamide (4b). mp 279-281 °C; Purity by HPLC: 99 %; IR (KBr): 3061, 2985, 2857,

1711, 1687, 1596, 1573, 1456, 1122, 1082 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm

1.30-1.34 (t, J=7.48 Hz, 6H, CH3), 2.45 (s, 3H, CH3), 3.50-3.55 (q, J=7.12 Hz, 4H, CH2),


J=9.88 Hz, 1H, ArH), 9.42 (s, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 12.61,

14.41, 20.15, 39.38, 41.44, 114.30, 115.60, 116.85, 118.11, 126.30, 127.41, 129.10,

129.15, 132.22, 132.30, 134.27, 147.13, 157.42, 162.81, 164.46, 164.90, 182.11; MS: m/z

= 354 [M+1]+; Anal. Calcd for C20H20FN3O2: C, 67.97; H, 5.70; N, 11.89. Found: C,

67.37; H, 5.63; N, 11.81%.

1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(4-phenylpiperazin-4-

yl)ethane-1,2-dione (4c). mp 223-225 °C; IR (KBr): 3088, 2976, 2864, 1702, 1683,

1601, 1589, 1471, 1134, 1084 cm-1; MS: m/z = 443 [M+1]+; Anal. Calcd for

C26H23FN4O2: C, 70.57; H, 5.24; N, 12.66. Found: C, 70.06; H, 5.14; N, 12.57%.

1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(piperidin-1-yl)ethane-

1,2-dione (4d). mp 193-195 °C; IR (KBr): 3070, 2968, 2842, 1718, 1699, 1581, 1578,

1459, 1113, 1079 cm-1; MS: m/z = 356 [M]+; Anal. Calcd for C21H20FN3O2: C, 69.03; H,

5.52; N, 11.50. Found: C, 68.84; H, 5.43; N, 11.41%.



1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(4-methylpiperazin-1-

yl)ethane-1,2-dione (4e). mp 275-277 °C; IR (KBr): 3084, 2951, 2823, 1710, 1681,

1600, 1589, 1423, 1196, 1089 cm-1; MS: m/z = 380 [M]+; Anal. Calcd for C21H21FN4O2:

C, 66.30; H, 5.56; N, 14.73. Found: C, 65.78; H, 5.40; N, 14.58%.

1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(4-ethylpiperazin-1-yl)

ethane-1,2-dione (4f). mp 212-214 °C; IR (KBr): 3075, 2956, 2846, 1699, 1680, 1586,

1579, 1485, 1096, 1086 cm-1; MS: m/z = 394 [M]+; Anal. Calcd for C22H23FN4O2: C,

66.99; H, 5.88; N, 14.20. Found: C, 66.26; H, 5.73; N, 14.01%.

1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(N,N-diisopropyl-1-yl)

ethane-1,2-dione (4g). mp 187-189 °C; IR (KBr): 3082, 2958, 2875, 1701, 1689, 1596,


69.27; H, 6.34; N, 11.02. Found: C, 68.53; H, 6.13; N, 10.88%.

1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(pyrrolidin-1-yl)

ethane-1,2-dione (4h). mp 238-239 °C; IR (KBr): 3089, 2971, 2853, 1709, 1700, 1588,

1564, 1443, 1191, 1087 cm-1; MS: m/z = 352 [M+1]+; Anal. Calcd for C20H18FN3O2: C,

68.36; H, 5.16; N, 11.96. Found: C, 67.57; H, 5.05; N, 11.79%.

1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(2-methylpiperidin-1-

yl)ethane-1,2-dione (4i). mp 166-168 °C; IR (KBr): 3070, 2954, 2856, 1706, 1602, 1582,


69.64; H, 5.84; N, 11.07. Found: C, 69.06; H, 5.71; N, 10.86%.

1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(4-methylpiperidin-1-

yl)ethane-1,2-dione (4j). mp 144-145 °C; IR (KBr): 3071, 2952, 2864, 1708, 1694, 1584,


69.64; H, 5.84; N, 11.07. Found: C, 68.87; H, 5.73; N, 10.88%.




HPLC of compound 4a





Minutes0 2 4 6 8 10 12 14 16 18 20

mAU

0

1000

2000

1.83

5 5

4328

0.1

02.

101

655

074

1.2

42.

496

593

64 0

.11

2.85

9 3

4625

0.0

7

3.60

5 2

4977

0.0

5

4.51

2 2

4576

5 0

.47

5.16

3 2

5403

7 0

.48

6.62

4 5

1400

831

97.

40

5007501000125015001750200025003000350040001/cm

0

15

30

45

60

75

90

%T 3116

.11

2979

.16

2942

.51

2856

.67

1729

.24

1708

.02

1627

.97

1528

.64

1442

.80

1365

.65

1299

.10

1254

.74

1238

.34

1207

.48

1154

.43

1090

.78

985.

6695

2.87

908.

5085

3.53

818.

8177

4.45

673.

1863

8.46

569.

02

reaction-91-R

N

NF

CH3OO

N

O





N

NF

CH3OO

N

OM.Wt. = 367.37

N

NF

CH3OO

N

N

M.Wt. = 442.48





N

NF

CH3OO

N

O





N

NF

CH3OO

NCH3CH3





N

NF

CH3OO

N

O

N

NF

CH3OO

NCH3CH3



Table-4b: Antimicrobial activity of 1-[2-(4-Fluorophenyl)-6-methylimidazo [1,2-a]


Sr. No.




4a 100 200 250 250 1000 >1000 >1000 4b 200 200 200 100 250 500 250 4c 100 100 100 200 500 500 200 4d 200 250 100 100 250 1000 1000 4e 250 200 50 200 >1000 1000 500 4f 500 100 250 100 1000 250 200 4g 250 200 500 500 500 500 250 4h 250 500 500 250 250 200 1000 4i 200 200 100 100 500 200 500 4j 500 200 250 200 200 250 200











REFERENCES

1. S. Howard, In Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees,

Scriven, E. V. F., Eds.; Pergamon: London, Vol. 8, Chapter 10, pp 262-274 (1996).

2. D. R. Sliskovic, In Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees,

Scriven, E. V. F., Eds.; Pergamon: London, Vol. 8, Chapter 12, pp 345-365 (1996).

3. I. Bennacef, C. N. Haile, A. Schmidt, A. O. Koren, J. P. Seibyl, J. K. Staley, F. Bois, R. M.

Baldwin, G. Tamagnan, Bioorg. Med. Chem., 14(22), 7582-7591 (2006).

4. F. Stefania, D. G. Sara, D. L. Laura, B. M. Letizia, D. Zeger, C. Alba, Heterocycles, 78(4),

947-959 (2009).

5. R. Max, R. Armin, D. Giusep, P. Kyoung, PCT Int. WO 2002014306A1 20020221, (2002).

6. T. Eszter, V. Csilla, S. Rita, K. Laszlo, Tet. Lett., 48(14), 2453-2456 (2007).

7. B. Roman, K. Lukasz, Syn. Comm., 23(22), 3149-3155 (1993).

8. L. K. Tin, S. M. Hsiu, H. H. Wen, H. C. Jeui, Synthesis, (9), 715-717 (1988).

Part – B

(Part – II)

Studies on Mannich base Derivatives


Mannich base derivatives… 109

INTRODUCTION

Mannich bases containing bridged N-atom exhibit pronounced biological

activities. The study of mannich reaction attracted a great deal of attention to the chemists

because it plays a vital role due to their wide range of biological and industrial

applications. Mannich bases are also employed as intermediate in chemical synthesis.1-3

Much interest has been focused on the synthesis of mannich bases due to its wide

a variety of pharmacological activities. Mostly, they are found to be antineoplastic,

analgesic and antibiotic drugs. Several therapeutic important molecules prepared through

mannich reaction have received more attention in recent years.4-6 Mannich bases have

gained important because of their technological application in polymer chemistry,7

especially as paints and surface active agent and it also exhibits complexation

characteristic with many transition metal ions.

SYNTHETIC ASPECT

Different methods have been cited to synthesize some new mannich bases by

several coworkers using various interesting substrates.

1. Gabriela Laura Almajan et al.8 have synthesized mannich bases (1) from some

triazole moiety.

X SO

O

N NH

N SN

Ar

X SO

O

N N

N SN

Ar

NO

morpholine, CH2O

X=H,Cl

37 % reflux

(1)

2. Y. Sumalatha et al.9 have synthesized mannich base (2) of imidazo[1,2-a]pyridine

moiety.

N

N

CH3

CH3 N

NCH3

NCH3

CH3

CH3COOH

formaline, RT

(2)

3. A. Katsifis et al.10 have prepared mannich bases (3) of imidazo[1,2-a]pyridine.



N

N

AR3

B HCHON

N

AR3

Me2N

B

(3) 4. Several new aminobenzylated mannich bases (4) have been prepared by

condensing reaction between heterocyclic secondary amines, aldehydes and

acetamide, urea and thiourea.11

X NH

HO

R C

O

NH2 CH3

X NH

OH X NH

NH NHH

N XO

R R(4)

R=ArylX=O/CH2

+

Over the years there has been much controversy about the mechanism of the

mannich reaction. Studies of the reaction kinetics have led to the following mechanistic

proposals.

REACTION MECHANISM

The mechanism of the Mannich reaction starts with the formation of an iminium

ion from the amine and the formaldehyde.

O

H

HH

+

O+

H

HH

N R2

R1

HO

H

HH

N+

R1

R2

H -H+

O

H

HH

N

R1

R2

H+

N+

R1

R2

H

H

-H2OO

+

H

HH

H

N

R1

R2



Because the reaction takes place under acidic conditions, the compound with the

carbonyl functional group (in this case a ketone) can tautomerize to the enol form, after

which it can attack the iminium ion.

R3

OR

4

HH

H+

R3

O+

R4

HH

H

-H+ OH

R3

H

R4

OH

R3

H

R4

+ N+

R1

R2

H

H R3

O+

HN

R1

R2

H

HH

R4

-H+

R3

O

N

R1

R2

H

HH

R4


A wide variety of pharmacological properties and industrial applications have

been encountered with several mannich bases such as,

1. Antibacterial12

2. Antitumor13


4. Cytotoxic Activity15

5. AntiHIV16

6. Antimalarial17

7. Antiproliferation18

8. Antiparasitic19

9. Antitubercular20

10. Antifungal21

11. Anticancer22

Several therapeutic important molecules containing heterocyclic secondary

amines are well known. For example, Manafflazineis a famous antiarthritic agent and

Minorine is used as antidepressant.

S. K. Sridhar23 have synthesized some new mannich bases and screened for anti-

inflammatory activity. A. R. Bhat et al.24 have reported mannich bases of quinoxaline and

evaluated for their antibacterial, antifungal and antitubercular activities.



P. Y. Shirodkar and M. M. Vartak25 have studied the antitubercular activity of

mannich bases of 6-nitro-3-N-arylaminomethyl-1,2,3,4-tetrahydro-4-oxo-2-thioqui-

noxalines (5).

N

NH

O2N

O

NH

R

(5)

Craig J. Roxburgh et al.26 have reported mannich bases and tested them for local

anesthetic activity (6).

H

S

O

O

N

(6)

Christina Reichwald et al.27 have synthesized mannich bases of 9-tert-butyl-2-

phenylethinylpaullone (7) from 1,3-diarylpropenones using aromatic aldehydes and

acetophenone derivatives as starting materials and studied their antileishmanial activity.

NH O

C(CH3)3

(7)

Yan Huang, et al.28 have synthesized some mannich bases and reported as

anticancer agent. Ya. L. Garazd et al.29 have prepared mannich bases of hydroxyl-

coumarines (8) which posses various biological activities.



O

N

X

O

OH

(8)

X = NCH3


K. S. Nimavat30 have synthesized some new aminobenzylated mannich bases

and reported as an antimicrobial agent. Study of mannich bases of 4-amino-3-

mercapto-5-pyridin-3'-yl-[1,2,4]-triazole reported by T. K. Dave.31 Green chemistry

approach to potentially bioactive aminobenzylated mannich bases through active

hydrogen compounds reported by S. L. Vasoya.32

Thus with an effort to capitalize the biological potential of the heterocyclic

system and to provide more interesting compounds for biological screening, we have

under taken the synthesis of several mannich bases which has been described as under.

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(4-

FLUOROPHENYL)-6-METHYL-3-(N,N-DIALKYLAMINE-4-YL

METHYL) IMIDAZO[1,2-a]PYRIDINES.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(4-

FLUOROPHENYL)-6-METHYL-3-(N,N-DIALKYLAMINE-4-YLMETHYL)

IMIDAZO[1,2-a]PYRIDINES.

Encouraged by earlier positive result in respect of mannich bases compounds have

gained lot of interest in last several year due to their biological, physiological and

industrial importance, based on extensive studies of pharmacological properties, it was

thought of interest to synthesize some new mannich bases by condensation of 2-(4-

fluorophenyl)-6-methylimidazo[1,2-a]pyridine with different secondary amines and

formaldehydes in the presence of acid catalyst.

REACTION SCHEME

N

NF

CH3N

NF

CH3

R

MeOH

HCHOSec. amine





















See Part-B, Part-I, Section-I, Experimental section [A].

[B] General procedure for the preparation of 2-(4-Fluorophenyl)-6-methyl-3-

(N,N-dialkylamine-4-ylmethyl)imidazo[1,2-a]pyridines.

To a solution of 2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (2.26 g,

0.01 mol), formaldehyde (0.3 g, 0.01 mol) and different secondary amine (0.01 mol) in

methanol (20 ml) was added and the reaction mixture was refluxed with stirring in the

presence of 1-2 drop concentrated HCl. After completion of reaction (monitoring by

TLC) cool the reaction mass and add ice cold water and extracted with ethyl acetate. The

organic layer was washed with water (2 x 10 ml) and dried with Na2SO4, solvent was

removed in vacuo and the resulting crude product was pure by colum chromatography to

give the analytical pure compound. The physical constants of the product are recorded in

Table-5a.

[C] Biological evaluation of 2-(4-Fluorophenyl)-6-methyl-3-(N,N-dialkylamine-4-






Table-5a: Physical constant of 2-(4-Fluorophenyl)-6-methyl-3-(N,N-dialkylamine-4-


N

NF

CH3

R


5a N O

C19H20FN3O

325.28 75 0.56

5b NCH3

CH3

C19H22FN3

311.39 78 0.39

5c N N

C25H25FN4

400.49 81 0.46

5d N

C20H22FN3

323.40 69 0.62

5e NCH3

CH3

CH3

CH3

C21H26FN3

339.44 73 0.48

5f N NCH3

C21H25FN4

352.44 86 0.36

5g

N N CH3

C20H23FN4

338.42 80 0.53

5h

N

C19H20FN3

309.38 79 0.57

5i N

CH3

C21H24FN3

337.43 70 0.61

5j N CH3

C21H24FN3

337.43 73 0.44




ANALYTICAL DATA

2-(4-Fluorophenyl)-6-methyl-3-(morpholin-4-ylmethyl)imidazo[1,2-a]pyridine (5a).

mp 183-185 °C; Purity by HPLC: 98 %; IR (KBr): 3114 (Ar, C-H str), 3009 (C-H str),

2956 (C-H str), 1657 (C=N str), 1576 (Ar, C=C str), 1460 (Ar, C=C str), 1345 (C-H str),

1214 (C-N str), 1158 (C-F), 841 (C-H, o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ

ppm 2.29 (s, 3H, CH3), 2.38-2.40 (t, J=4.44 Hz, 4H, 2CH2), 3.58-3.61 (t, J=4.52 Hz, 4H,

2CH2), 3.81 (s, 2H, CH2), 6.98-7.01 (m, 1H, ArH), 7.03-7.08 (m, 2H, ArH), 7.45-7.47 (d,

J=9.12 Hz, 1H, ArH), 7.68-7.72 (m, 2H, ArH), 8.06 (s, 1H, ArH). 13C NMR (100 MHz,

CDCl3): δ ppm 18.55, 51.94, 53.18, 66.97, 115.29, 115.50, 116.55, 121.68, 122.66,

127.93, 130.43, 130.51, 130.66, 130.69, 144.08, 144.18, 161.29, 163.74; MS: m/z = 326

[M+1]+; Anal. Calcd for C19H20FN3O: C, 70.13; H, 6.20; N, 12.91. Found: C, 69.83; H,

6.13; N, 12.76%.

N-Ethyl-N-{[2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}

ethanamine (5b). mp 147-148 °C; Purity by HPLC: 99 %; IR (KBr): 3072, 2980, 2862,

1603, 1554, 1434, 1456, 1119, 1035, 820 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 0.99-

1.03 (t, J=7.08 Hz, 6H, CH3), 2.29 (s, 3H, CH3), 2.46-2.52 (q, J=7.2 Hz, 4H, CH2), 3.98

(s, 2H, CH2), 6.99-7.02 (m, 1H, ArH), 7.06-7.09 (m, 2H, ArH), 7.52-7.54 (d, J=10.56 Hz,

1H, ArH), 7.74-7.78 (m, 2H, ArH), 8.10 (s, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ

ppm 13.11, 21.68, 50.93, 52.18, 115.50, 115.80, 116.75, 122.20, 123.30, 128.50, 130.80,

130.99, 131.06, 131.10, 144.48, 144.60, 161.80, 164.12; MS: m/z = 311 [M]+; Anal.

Calcd for C19H22FN3: C, 73.28; H, 7.12; N, 13.49. Found: C, 72.53; H, 7.03; N, 13.33%.

2-(4-Fluorophenyl)-6-methyl-3-[(4-phenylpiperazin-1-yl)methyl]imidazo[1,2-a]

pyridine (5c). mp 192-194 °C; IR (KBr): 3080, 2968, 2835, 1599, 1574, 1481, 1463,

1138, 1043, 850 cm-1; MS: m/z = 400 [M]+; Anal. Calcd for C25H25FN4: C, 74.97; H,

6.29; N, 13.99. Found: C, 74.21; H, 6.07; N, 13.75%.

2-(4-Fluorophenyl)-6-methyl-3-(piperidin-1-ylmethyl)imidazo[1,2-a]pyridine (5d).

mp 198-199 °C; IR (KBr): 3076, 2961, 2863, 1645, 1542, 1453, 1378, 1143, 1037, 832

cm-1; MS: m/z = 325 [M+2]+; Anal. Calcd for C20H22FN3: C, 74.28; H, 6.86; N, 12.99.

Found: C, 74.05; H, 6.77; N, 12.71%.

N-{[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}-N-isopropyl

propan-2-amine (5e). mp 124-126 °C; IR (KBr): 3084, 2967, 2857, 1605, 1559, 1462,



1376, 1134, 1054, 845 cm-1; MS: m/z = 339 [M]+; Anal. Calcd for C21H26FN3: C, 74.30;

H, 7.72; N, 12.38. Found: C, 73.17; H, 7.59; N, 12.26%.

2-(4-Fluorophenyl)-6-methyl-3-[(4-ethylpiperazin-1-yl)methyl]imidazo[1,2-a]

pyridine (5f). mp 223-224 °C; IR (KBr): 3078, 2959, 2886, 1612, 1551, 1487, 1389,

1144, 1046, 848 cm-1; MS: m/z = 353 [M+1]+; Anal. Calcd for C21H25FN4: C, 71.56; H,

7.15; N, 15.90. Found: C, 71.34; H, 7.01; N, 15.72%.

2-(4-Fluorophenyl)-6-methyl-3-[(4-methylpiperazin-1-yl)methyl]imidazo[1,2-a]

pyridine (5g). mp 173-175 °C; IR (KBr): 3097, 2956, 2872, 1611, 1534, 1456, 1451,

1129, 1034, 865 cm-1; MS: m/z = 339 [M+1]+; Anal. Calcd for C20H23FN4: C, 70.98; H,

6.85; N, 16.56. Found: C, 70.83; H, 6.74; N, 16.47%.

2-(4-Fluorophenyl)-6-methyl-3-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridine (5h).

mp 144-145 °C; IR (KBr): 3082, 2954, 2868, 1614, 1559, 1446, 1471, 1139, 1043, 870

cm-1; MS: m/z = 309 [M]+; Anal. Calcd for C19H20FN3: C, 73.76; H, 6.52; N, 13.58.

Found: C, 72.32; H, 6.29; N, 13.45%.

2-(4-Fluorophenyl)-6-methyl-3-[(2-methylpiperidin-1-yl)methyl]imidazo[1,2-a]

pyridine (5i). mp 153-155 °C; IR (KBr): 3046, 2964, 2834, 1621, 1558, 1448, 1356,


7.17; N, 12.45. Found: C, 74.37; H, 7.05; N, 12.36%.

2-(4-Fluorophenyl)-6-methyl-3-[(4-methylpiperidin-1-yl)methyl]imidazo[1,2-a]

pyridine (5j). mp 134-136 °C; IR (KBr): 3089, 2956, 2885, 1625, 1545, 1446, 1426,


7.17; N, 12.45. Found: C, 74.36; H, 7.09; N, 12.31%.




HPLC of compound 5a





Minutes0 1 2 3 4 5 6 7 8 9 10

mA

U

0

500

1000

1.82

4 1

2825

1 0

.87

2.41

1 1

4475

616

98.

18

3.46

7 3

0266

0.2

1

7.92

5 3

5674

0.2

4

8.36

3 2

4485

0.1

7

9.29

1 4

9833

0.3

4

5007501000125015001750200025003000350040001/cm

30

45

60

75

90

105

%T

3114

.18

3009

.05

2956

.01 29

02.9

6

1657

.87

1576

.86 15

18.0

3 1502

.60

1460

.16

1419

.66

1345

.39

1324

.18

1305

.85

1257

.63

1214

.23

1158

.29

1114

.89

1029

.06

986.

6284

1.96 82

0.74

731.

0570

8.86

508.

26

4-NO2-chal

N

NF

CH3

N

O





N

NF

CH3

N

O

M. Wt. = 325.38

N

NF

CH3

N

N

M. Wt. = 400.49





N

NF

CH3

N

O





N

NF

CH3

N

CH3

CH3





N

NF

CH3

N

O

N

NF

CH3

NCH3

CH3



Table-5b: Antimicrobial activity of 2-(4-Fluorophenyl)-6-methyl-3-(N,N-dialkyl-

amine-4-ylmethyl)imidazo[1,2-a]pyridines.

Sr. No.




5a 100 100 250 250 200 1000 1000 5b 100 200 100 500 250 500 250 5c 250 250 250 125 500 1000 1000 5d 200 250 125 500 1000 250 500 5e 250 200 500 500 500 1000 1000 5f 100 62.5 100 200 500 200 500 5g 200 500 62.5 250 250 500 250 5h 500 250 500 200 200 200 500 5i 200 500 200 100 500 200 250 5j 500 200 250 250 500 250 200











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Part – B

(Part – III)

Studies on Bis-imidazo[1,2-a]pyridin Derivatives


Bis imidazo[1,2-a]pyridine derivatives… 127

INTRODUCTION

Bis imidazo[1,2-a]pyridine (1) is an aromatic heterocyclic organic compound

having one carbon atom is common with attached two imidazo[1,2-a]pyridine ring

system. Hence they are interesting target to be prepared to our research on medicinally

interesting heterocyclic entities.

N

N

N

N(1)

As evident from the literature in recent years a significant portion of research

work in heterocyclic chemistry has been devoted to bis imidazo[1,2-a]pyridine containing

different aryl, alkyl and heteroaryl groups as substituent.

SYNTHETIC ASPECT

Various methods for the preparation of dimer have been cited in literature, some

of the methods are as under.

1. R. Zhang et al.1 synthesized bis-imidazo[1,2-a]pyridinylmethanes from imidazole

with different aryl aldehydes.

N

NR

1

HO

RN

NR

1

N

N

R1 R+

2. Y. Sumalatha and coworkers2 have been reported bis-imidazo[1,2-a]pyridine

substances as hypnotic agent.

N

NCH3

CH3

OH

N

NCH3

CH3 N

N

N

N

CH3

CH3

CH3

CH3

+



3. J. C. Teulade and coworkers3 have been reported some bis imidazo[1,2-a]azines

from acetaldehyde.

N

NN

NN

N

CH3

CH3 CH ON

N

OHCH3

4. K. Asakawa et al.4 have synthesized bis benzimidazoles and reported alternative

preparation shown in-situ reaction.

N

NH

O

O

CH3NH

N

N

NH

COH

+

5. M. Fabio da Silva and coworkers5 have reported new method for the preparation

of bis(1H-benzimidazol-2-yl)methanone.

NH2

NH2

O

OEt

O

OEtNH

N

NH

N

+

6. W. Oi and coworkers6 synthesized phenyl bis indole and reported selective

receptor for chloride anion.

NH

CH3O

NH

CH3

NH

CH3

+

7. G. V. Ramin, et al.7 synthesized bis(indolyl)methanes in water and also

synthesized di-, tri-, and tetra(bis-indolyl)methanes under thermal conditions

catalyzed by oxalic acid dehydrate.



O

OCH3 N

H

(CH2)3 COOH

NH

NH (CH2)3

(CH2)3HOOC

COOH

OCH3

+

8. G. K. P. Surya and coworkers8 reported microwave assisted synthesis of

triarylmethanes by using Nafion-H catalyst.

O

+



been encountered with several dimer such as,

1. Antimicrobial9


3. Anti cancer11

4. Analgesic12

5. Antifungal13

6. Anti-HIV14

7. Anti protozoal15

8. Anti malarial16

9. Cytotoxic Activity17

10. Anti tumor18

N. P. Kozyreva and coworkers19 synthesized co-bis benzo[g]quinol (2) derivatives

and tested their antimalarial activity. A. O. Abdelhamid et al.20 have reported

antimicrobial evaluation of synthesized compound. L. S. Fernandez et al.21 have reported

synthesis of bis-indole alkaloids from flindersia species and their antimalarial activity.



NN (CH2)n N N

NN (2)

R. Rohini et al.22 have synthesized bis-indolo[1,2-c]quinazolines (3) and evaluated

them for antimicrobial studies. L. Dassonneville et al.23 reported plant alkaloid

usambarensine intercalates into DNA and induces apoptosis in human HL60 leukemia

cells.

NN

X

NN

(3)

K. Oh et al.24 have reported synthesis and antimicrobial activities of halogenated

bis(hydroxyphenyl)methanes (4). C. S. Reddy and coworkers25 have synthesized and

evaluated novel bis[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles as potent antimicrobial agents.

S. M. Sondhi and coworkers26 reported biological activity of novel bis Schiff bases, bis

hydrazone and bis guanidine derivatives.

OH OH

Cl

Cl Cl

Cl

(4)

K. V. Sashidhara et al.27 have synthesized and reported antihyperlipidemic activity

of novel coumarin bisindole (5) derivatives. X. H. Gu et al.28 synthesized and reported

biological activities of bis(3-indolyl)thiazoles, analogs of marine bis(indole)alkaloid

nortopsentins. G. A. Youngdale et al. synthesized 5-substituted 2,3-bis(p-methoxyphenyl)

indoles and reported their antiinflammatory activity. C. Praveen and coworkers29 have

documented bis(indolyl)methanes and evaluated of their antimicrobial and antioxidant



activity. S. Ahn and coworkers30 reported a novel bis-indole destabilize microtubules and

displayed potent in vitro and in vivo antitumor activity in prostate cancer.

NH

OO

CO2Et

NH

(5)

M. A. Ismail and coworkers31 have reported synthesis and antiprotozoal activity of

novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-

a]pyridines. M. R. Jacobs et al.32 have prepared some novel bis-indole agents active

against multidrug resistant acinetobacter baumannii. B. B. Dey et al.33 reported a

coumarin dimer directly linked without any bridge. R. Rohini and coworkers34 presented

bis-6-arylbenzimidazo[1,2-c]quinazolines, a new class of antimicrobial agents.



under taken the synthesis of several dimer which has been described as under.

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(4-

FLUROPHENYL)-3-((2-(4-FLUROPHENYL)-6-METHYLH-

IMIDAZO[1,2-a]PYRIDINE-3-YL)(ARYL)METHYL)-6-METHYL

H-IMIDAZO[1,2-a]PYRIDINES.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(4-FLUROPHENYL)-3-

((2-(4-FLUROPHENYL)-6-METHYLH-IMIDAZO[1,2-a]PYRIDINE-3-YL)

(ARYL)METHYL)-6-METHYL H-IMIDAZO[1,2-a]PYRIDINES.

Bis imidazo[1,2-a]pyridine derivatives are important intermediates in organic

synthesis, especially in the synthesis of biologically active and medicinally useful agents.

For instance, they are widely used in the synthesis of cyclin-dependent kinases (CDK)

inhibitors, sleep inducers, anticonvulsant agents, etc. The synthesis of some new

potentially bioactive bis imidazo[1,2-a]pyridine derivatives have been show in reaction

scheme.

REACTION SCHEME

N

NF

CH3 N

NF

CH3

N

NF

CH3R

acetic acid

R-CHO





















See Part-B, Part-I, Section-I, Experimental section [A].

[B] General procedure for the preparation of 2-(4-Fluorophenyl)-3-((2-(4-

fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)(aryl)methyl)-6-methyl

H-imidazo[1,2-a]pyridines.

To a mixture of 2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (4.52 g,

0.02 mol) and aromatic aldehydes (0.01 mol) in acetic acid (4 ml), sodium acetate 1.0 g

was added and refluxed for 24 hour (monitoring by TLC). After cooling to room

temperature, the reaction mixture was diluted with water and made basic with saturated

sodium carbonate solution. The solution was extracted with dichloromethane and the

organic layer was dried over anhydrous Na2SO4. After the solvent was evaporated, the

residue was chromatographed on silica gel (eluent 6 : 4 = E.A. : Hexane) to give

analytical pure products. The physical constants of the product are recorded in Table-6a.

[C] Biological evaluation of 2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH

-imidazo[1,2-a]pyridin-3-yl)(aryl)methyl)-6-methylH-imidazo[1,2-a]

pyridines.





Table-6a: Physical constant of 2-(4-Flurophenyl)-3-((2-(4-flurophenyl)-6-methylH-

imidazo[1,2-a]pyridine-3-yl)(aryl)methyl)-6-methylH-imidazo[1,2-a]

pyridines.

N

NF

CH3

N

NF

CH3 R


6a CH3

C36H28F2N4

554.63 73 0.52

6b S

C33H24F2N4S

546.63 67 0.54

6c

C35H26F2N4

540.60 72 0.48

6d N+

O-

O

C35H25F2N5O2

585.60 65 0.38

6e Cl

C35H25ClF2N4

575.04 71 0.42

6f NH2

C35H27F2N5

555.61 78 0.58

6g F

C35H25F3N4

558.59 63 0.61

6h Br

C35H25BrF2N4

619.50 72 0.45

6i OCH3

C36H28F2N4O

570.63 78 0.57

6j OH

C35H26F2N4O

556.60 81 0.35




ANALYTICAL DATA

2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)(p-

tolyl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6a). mp 161-163 °C; Purity by

HPLC: 87 %; IR (KBr): 3069 (Ar, C-H str), 2920 (C-H str), 2862 (C-H str), 1616 (C=N

str), 1534 (Ar, C=C str), 1464 (Ar, C=C str), 1340 (C-H ban), 1179 (C-N str), 1089 (C-F),

845 (C-H o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 2.34 (s, 3H, CH3), 2.44 (s,

6H, CH3), 5.34 (s, 1H, CH), 7.03-7.05 (m, 2H, ArH), 7.08-7.16 (m, 4H, ArH), 7.20-7.24

(m, 2H, ArH), 7.51-7.52 (d, J=7.16 Hz, 2H, ArH), 7.53-7.55 (d, J=9.2 Hz, 2H, ArH),

7.72-7.80 (m, 4H, ArH), 7.88-7.92 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm

18.15, 21.74, 40.49, 107.54, 115.57, 115.78, 116.63, 122.41, 123.36, 127.59, 127.67,

128.31, 129.76, 144.30, 144.55, 163.91; MS: m/z = 554 [M]+; Anal. Calcd for

C36H28F2N4: C, 77.96; H, 5.09; N, 10.10. Found: C, 76.31; H, 4.87; N, 10.03%.

2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)

(thiophen-2-yl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6b). mp 192-193 °C;

Purity by HPLC: 84 %; IR (KBr): 3068, 2977, 2823, 1600, 1576, 1435, 1377, 1150, 1067,

840 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 2.52 (s, 6H, CH3), 5.41 (s, 1H, CH), 6.54-


ArH), 7.19-7.23 (m, 2H, ArH), 7.31-7.58 (m, 2H, ArH), 7.74-7.79 (m, 4H, ArH), 7.95-

7.99 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 19.17, 41.12, 104.24, 111.40,

111.78, 112.90, 126.67, 126.80, 127.44, 129.04, 139.64, 140.46, 146.93, 147.14, 164.33;

MS: m/z = 546 [M]+; Anal. Calcd for C33H24F2N4S: C, 72.51; H, 4.43; N, 10.25. Found:

C, 71.78; H, 4.38; N, 10.07%.

2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)

(phenyl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6c). mp 175-177 °C; IR (KBr):

3099, 2975, 2849, 1599, 1557, 1439, 1366, 1134, 1054, 842 cm-1; MS: m/z = 541 [M+1]+;

Anal. Calcd for C35H26F2N4: C, 77.76; H, 4.85; N, 10.36. Found: C, 77.17; H, 4.71; N,

10.23%.

2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)(4-

nitrophenyl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6d). mp 209-211 °C; IR

(KBr): 3081, 2966, 2843, 1634, 1584, 1446, 1366, 1240, 1138, 1031 cm-1; MS: m/z = 585



[M]+; Anal. Calcd for C35H25F2N5O2: C, 71.79; H, 4.30; N, 11.96. Found: C, 70.70; H,

4.17; N, 11.79%.

3-((4-Chlorophenyl)(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)

methyl)-2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (6e). mp 203-204 °C;

IR (KBr): 3087, 2988, 2867, 1616, 1558, 1467, 1346, 1135, 1021, 720 cm-1; MS: m/z =

577 [M+2]+; Anal. Calcd for C35H25ClF2N4: C, 73.10; H, 4.38; N, 9.74. Found: C, 72.18;

H, 4.26; N, 9.66%.

4-(Bis(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)methyl)

benzenamine (6f). mp 185-187 °C; IR (KBr): 3490, 3073, 2973, 2864, 1611, 1567, 1454,

1386, 1138, 1036 cm-1; MS: m/z = 556 [M+1]+; Anal. Calcd for C35H27F2N5: C, 75.66; H,

4.90; N, 12.60. Found: C, 75.18; H, 4.77; N, 12.43%.

2-(4-Fluorophenyl)-3-((4-fluorophenyl)(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-

a]pyridin-3-yl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6g). mp 232-234 °C; IR

(KBr): 3090, 2961, 2853, 1614, 1546, 1467, 1369, 1129, 1043 cm-1; MS: m/z = 558 [M]+;

Anal. Calcd for C35H25F3N4: C, 75.26; H, 4.51; N, 10.03. Found: C, 74.83; H, 4.25; N,

9.83%.

3-((4-Bromophenyl)(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)

methyl)-2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (6h). mp 226-228 °C;

IR (KBr): 3088, 2976, 2858, 1606, 1568, 1434, 1374, 1144, 1046, 840 cm-1; MS: m/z =

619 [M]+; Anal. Calcd for C35H25BrF2N4: C, 67.86; H, 4.07; N, 9.04. Found: C, 67.33; H,

3.83; N, 9.00%.

2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)(4-

methoxyphenyl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6i). mp 157-159 °C; IR

(KBr): 3087, 2973, 2851, 1600, 1587, 1446, 1379, 1099, 1063 cm-1; MS: m/z = 570 [M]+;

Anal. Calcd for C36H28F2N4O: C, 75.77; H, 4.95; N, 9.82. Found: C, 75.15; H, 4.58; N,

9.53%.

4-(Bis(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)methyl)phenol (6j).

mp 177-178 °C; IR (KBr): 3440, 3082, 2946, 2864, 1609, 1579, 1446, 1378, 1149, 1081

cm-1; MS: m/z = 557 [M+1]+; Anal. Calcd for C35H26F2N4O: C, 75.52; H, 4.71; N, 10.07.

Found: C, 74.67; H, 4.47; N, 9.84%.




HPLC of compound 6a





Minutes0 1 2 3 4 5 6 7 8 9 10 11 12

0

50

100

1.24

8 2

2122

1.7

4

1.70

7 5

887

0.4

61.

813

315

0 0

.25

2.06

9 4

6010

3.6

2

2.60

3 1

1146

34 8

7.75

3.48

8 4

9490

3.9

0

4.37

3 2

1377

1.6

8

6.41

1 2

019

0.1

6

7.28

5 3

502

0.2

8

7.89

3 2

011

0.1

6

5007501000125015001750200025003000350040001/cm

30

45

60

75

90

105

%T

3069

.81

3003

.27

2920

.32

2868

.24

1616

.40

1588

.43

1534

.42

1464

.02

1424

.48

1340

.57

1301

.03

1179

.51

1148

.65

1123

.57

1089

.82

1050

.28

1007

.84

988.

5596

3.48

845.

8180

7.24

751.

3067

8.97

581.

5653

4.30

475.

4742

725

JP-104

N

N

N

N

CH3

F

F

CH3CH3



Mass spectrum of compound 6b


N

N

N

N F

F

CH3CH3

M. Wt. = 540.60

N

N

N

N F

F

CH3CH3 S

M. Wt. = 546.63





N

N

N

N

CH3

F

F

CH3CH3





N

N

N

N F

F

CH3CH3 S





N

N

N

N

CH3

F

F

CH3CH3

N

N

N

N F

F

CH3CH3 S



Table-6b: Antimicrobial activity of 2-(4-Flurophenyl)-3-((2-(4-flurophenyl)-6-

methylH-imidazo[1,2-a]pyridine-3-yl)(aryl)methyl)-6-methylH-imidazo

[1,2-a]pyridines.

Sr. No.




6a 250 500 100 500 250 500 1000 6b 200 100 250 100 200 1000 500 6c 50 100 250 100 1000 500 250 6d 250 250 500 500 500 250 500 6e 200 250 100 250 250 500 250 6f 500 250 200 100 200 250 250 6g 100 500 125 500 500 1000 500 6h 250 100 500 200 1000 500 250 6i 250 200 200 200 500 200 500 6j 125 100 250 100 250 250 250











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Part – C

Introduction

Studies on Thiophene Derivatives


Thiophene derivatives… 145

INTRODUCTION

Thiophene-2-carbaldehyde (1) is an aromatic heterocyclic compound consisting of

four carbon atoms and one sulfur atom in a five-membered ring. Thiophene was

discovered by Viktor Meyer in 1883 as a contaminant in benzene.1 Related to thiophene

are benzothiophene and dibenzothiophene, containing the thiophene ring fused with one

and two benzene rings.

It was observed that isatin forms a blue dye if it is mixed with sulfuric acid and

crude benzene. Victor Meyer was able to isolate the substance responsible for this

reaction from benzene. This new heterocyclic compound was thiophene.2

SO

(1)

Thiophenes are important class of heterocyclic compounds and are recurring

building blocks in organic chemistry with applications in pharmaceuticals. The benzene

ring of a biologically active compound may often be replaced by a thiophene without loss

of activity.3 Thiophene and its derivatives occur in petroleum, sometimes in

concentrations up to 1-3%. The thiophenic content of liquids from oil and coal is removed

via the hydrodesulfurization (HDS) process.

SYNTHETIC ASPECT

Various methods for the preparation of thiophene derivatives have been cited in

literature, some of the methods are as under.

1. Y. Kopylov and coworkers4 synthesized thiophene via butane, (methyldi-

sulfanyl)ethane, (ethyldisulfanyl)ethane and aluminum oxide as a catalyst.

CH3

CH3

CH3S S

CH3

Et SS Et

SAl2O3, 450 °C75 min+ +

2. Liang, Xinmiao and coworkers5 have synthesized thiophene using ferrous nitrate

and cynomethane.

S

OHSFe(NO3)3,CH3CN

12 hrs , RT



3. Moon, Jeongju and coworkers6 synthesized thiophenes and 2,2'-bithiophene using

sodium butoxide and cyclohexenone, palladium as catalyst.

S Br NaoBu, Cyclohexanol

Ph2,Pentadienone Pd

S S S+

4. N. T. Berberova et al.7 have synthesized thiophenes and thiophene-2-thiol via

dichloro methane and hydrogen sulphide at 20-25 °C.

O S SH SH2S, CH2Cl2

+

5. A. R. Katritzky et al.8 have synthesized thiophenes from 2,5-dimethylthiophene

using hydrophosphoric acid.

S CH3CH3

SH3PO4

6. E. N. Deryagina and coworkers9 synthesized thiophenes from 2-chlorothiophene

and ethyne.

S Cl S

CH CH


Over recent years there has been an increasing interest in the chemistry of

thiophene because of their biological significance.

1. Analgesic10

2. Antimicrobial11,12

3. Anticonvulsant13,14

4. Antifungal15

5. Antihistaminic16

6. Antiinflammatory17,18

7. Antitumor19,20

8. Antiviral21,22



9. Diuretic23

10. Insecticidal24

11. Antipsychotic25

12. Anticancer26,27

S. F. Mohmad28 have prepared {[4-(thiophen-2-yl)-3,4,5,6-tetrahydrobenzo

[H]quinazolin-2-yl]sulfanyl} acid (2) as a antiviral and anticancer agent.

NH

N

S

S

OOH

(2)

Gautam Panda29 have prepared 2-{phenyl[4-(2-phenylethoxy)phenyl] methyl}

thiophene (3) and tested for its antitubercular activity.

S

OR

(3)

M. S. Malamas and coworkers30 have synthesized novel thiophene derivatives

inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties. S. S.

Perez et al.31 developed 5-substituted thiophene derivatives with dual action at 5-HT1A

serotonin receptors and serotonin transporter as a new class of antidepressants. Synthesis

and serotonergic activity of thiophene-4-piperazine derivatives as novel antagonists for

the vascular 5-HT1B receptor has been achieved by G. P. Moloney and group.32

Derivatives of benzo[b]thiophene are also available as drug, some of them are

shown as under:



S

NOH NH2

O

Zileuton (ZYFLOTM)Antiashthamatic

S

OH

OH

O

ON

RaloxifeneAnticancer/Osteroporosis

S

Cl

O

NN Cl

Cl

SertaconazoleAntifungal


V. V. Kachhadia et al.33 have synthesized 6-carbethoxy-5-aryl-3-[p-(3'-chloro-2'-

benzo[b]thiophenoylamino)phenyl]-2-cyclohexenones derivatives bearing benzo[b]

thiophene nucleus and reported their antitubercular and antimicrobial activity.34

S. L. Vasoya et al.35 reported facile synthesis of some new azetidinones and acetyl

oxadiazoles as a potent biological active agent, he also synthesized thiosemicarbazides

and 1,3,4-thiadiazoles as potent antitubercular and antimicrobial agents,36 moreover he

has reported thiosemicarbazide and 1,2,4-triazoles heterocycles as a potent antitubercular

and antimicrobial agents37 bearing benzo[b]thiophene nucleus.

Prior art search reveals that thiophene derivatives are proved to be potent

biodynamic agents, for their various methods of synthesis and different biological

activities, synthesis of thiophene derivatives have been undertaken in order to achieving

superior therapeutic agents. This can be summarized in the following sections as under.

STUDIES ON THIOPHENE DERIVATIVES





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Part – C

(Part – I)

Studies on Pyrazoline Derivatives


Pyrazole derivatives… 151

INTRODUCTION

The chemistry of pyrazoles has been reviewed by Jarobe in 1967. Pyrazoles have

attracted attention of medicinal chemists for both with regard to heterocyclic chemistry

and the pharmacological activities associated with them. Pyrazole have been studied

extensively because of ready accessibility, diverse chemical reactivity, broad spectrum of

biological activity1 and varieties of industrial applications.2

Pyrazole has three possible tautomeric structures. But 2-pyrazole (1) consist a

unique class of nitrogen containing five member heterocycles.

NNH(1)

As evident from the literature in recent years a significant portion of research

work in heterocyclic chemistry has been devoted to pyrazoles containing different alkyl,

aryl and heteroaryl groups as substituents.

SYNTHETIC ASPECT

Different methods are available from the literature for the preparation of 2-

pyrazole derivatives. The most common procedure for the synthesis of 2-pyrazoles is the

reaction of an aliphatic or aromatic hydrazine with α,β-unsaturated carbonyl compounds.

R1

O

R2 NH2 NH

RN

NR

R2

R1

+

ALTERNATIVE SYNTHETIC ROUTES FOR IMPROVED YIELD, SHORTER

REACTION TIME AND MILDER CONDITIONS TO SYNTHESIZE NEW ANALOGS

Solid-Phase Synthesis

L. L. De3 reported cellulose beads as a new versatile solid support for microwave-

assisted synthesis of pyrazole and isoxazole libraries.



R

O

YOR

1

CSA (cat.)

MW

Cellulose

R

O

Y

OR

1

NHNH2XH

MW

XN R

YO R

1

N

N

CH(OCH3)2

Cellulose NH2

Cellulose NH2

Wang resin supported solid-phase synthesis of pyrazoledicarboxylic acid

derivatives by functionalization of cyanoformate was reported by C. F. Morelli et al.4

OH OCN

O

O

O N NR

3

R1

OO

R2

Similarly many other solid phase synthesis of pyrazole motif were reported using

different solid support such as (4-formyl-3-methyoxyphenoxy)methylpolystyrene (FMP)

resin,5 polymer-supported vinylsulfone,6 Kenner ‘safety catch’ resin,7 KOH powder.8

Liquid-Phase Synthesis

X. L. Ren and coworkers9 have synthesized pyrazole derivatives using liquid

phase synthesis strategy.

R

1

R2 R

NNHR

1

NH2R

NH2NH2 . HCl

V. N. Pathak and coworkers10,11 reported 3,5-diarylpyrazole synthesis using phase

transfer catalyst. Heterocyclic pyrazole was synthesized by the W. C. Shen and

coworkers.12

Microwave Assisted Synthesis

Microwave irradiation and solvent-free conditions was reported for the rapid and

efficient synthesis of pyrazole was reported by M. A. H. Zahran.13

R CHONH2

XH

MWNR

HOH

N

XR+



New "Green" approaches to the synthesis of pyrazole derivatives were reported by

A. Corradi et al.14

H

R H

OR

1

NH2NHTs, K2CO3

MW, 130 °C

H

R H

NR

1

NHTsNN

R

R1

H

Similarly in literature there are number of the reports for the use of microwave

irradiation for the rapid synthesis, high yield or towards the green approach of the

reaction under solvent free conditions. Some of them are reported as below.

S. S. Chauhan15 derived pyrazoles from diaryl 1,3-diketones, I. Rinski and

coworkers16 prepared 1,3-dipolar cycloaddition of diazo compounds to acetylene

derivatives, M. A. P. Martins et al.17 reported regiospecific synthesis of 5-trifluoromethyl-

4,5-dihydropyrazoles, H. S. P. Rao18 derived microwave mediated combinatorial

synthesis, S. A. Swelam19 derived pyrazole under dry media, M. A. P. Martins and

coworkers20 reported regiospecific synthesis of pyrazole, B. R. Rao and

coworkers21synthesis pyrazole by use of p-toluenesulphonic acid and S. Katade et al.22

reported microwave synthesis of pyrazole.

P. Kumar et al.23 have synthesized of pyrazole chalcones under solvent free

condition at room temperature. X. H. Liu et al.24 reported novel dihydropyrazole

derivatives linked with 4H-chromene.

Catalysts

Many of the organic chemists prefered to use catalyst to get the desire product

with high yield and within sort reaction time and to convert the reaction condition from

drastic to easily operational with some specific catalyst.

R. Ali reported stereoselective synthesis of N-vinyl pyrazoles in solvent-free

conditions using dipotassium hydrogen phosphate powder.25 Zinc-catalyzed syntheses of

pyrazolines and pyrazoles via hydrohydrazination were reported by K. Alex.26

NHNH2

OH 5 mol % Zn(OTf)2 NN CH3COOH, air N

N

RR R

+



In literature there are number of the catalysts are used for the synthesis of pyrazole

system like Conjugate base,27 Iodine(III),28 Hafnium chloride,29 Tungstophosphoric

acid,30 p-Toluenesulphonic acid,31 Sulfamic acid,32 Ytterbium(III)perfluorooctanoate,33

Silver(I),34 Organocatalysts.35

REACTION MECHANISM

The following mechanism seems to be operable for pyrazoline by the

condensation of chalcones with hydrazine hydrate.36

R

O

R1

R CH-

O

R1

NH2+NHR

2

NH2NH - R2. .

H+ transferR

C+

CH-

OH

R1

NHNHR

2

R

O

R1

NHNHR

2

N NH

R1

OHR

R2N N

H

R1

R2

R - H2O

( I ) ( II )

( III ) ( IV )( V )

Nucleophillic attack by hydrazine at the β-carbon of the α,β-unsaturated carbonyl

system (I) forms species (II), in which the negative charge is mainly accommodated by

the electronegative oxygen atom.

Proton transfer from the nitrogen to oxygen produces an intermediate and which

simultaneously ketonises to ketoamine (III). Another intramolecular nucleophillic attack

by the primary amino group of ketoamine on its carbonyl carbon followed by proton

transfer from nitrogen to oxygen leads ultimately to hydroxyl amine (IV). The later with a

hydroxy group and amine group on the same carbon loses water easily to yield the

pyrazolines (V).


From the literature survey, it was revealed that 2-pyrazolines are better therapeutic

agents. They possess valuable bioactivities like



1. Antiinflammatory37,38

2. Analgesic39,40

3. Bactericidal41

4. Fungicidal42,43

5. Anticonvulsant44

6. Pesticidal45,46

7. Antidepressant47

8. Antiamoebic48

9. Insecticidal49

10. Antineoplastic50,51

11. Herbicidal52

M. K. Shivnanda and coworkers53 have prepared pyrazolines and reported their

antibacterial activity. Antimicrobial activity of pyrazoline derivatives (2) have been

reported by K. N. Sharma et al.54 J. Almstead et al.55 have prepared pyrazolines as

vascularization agent. T. Z. Gulhan and coworkers56 have prepared pyrazolines as a

hypotensive agent.

NH

O

N NR2

R1

(2)

M. Q. Fan et al.57 have synthesized pyrazolines and tested their antidepressant

activity. Antiamoebic activity of pyrazoline derivatives have been reported by Asha

Budakoti and coworkers.58 J. H. Ahn et al.59 have reported cyanopyrazoline (3)

derivatives as potent antidiabetic agents. T. S. Jeong et al.60 have synthesized some novel

3,5-diaryl pyrazolines (4) as human acyl-Co A: cholesterol acyltransferase inhibitors. G.

Ucar et al.61 reported pyrazolines as cholinstearase andselective monoamine oxidase-B

inhibitiors for the treatment of parkinson and alzheimer’s diseases. M. N. Nasr et al.62

have reported the synthesis of newer arylthiazolylpyrazoline derivatives as

antiinflammatory agents. M. A. Berghot et al.63 have prepared for convergent synthesis

and antibacterial activity of pyrazole and pyrazoline derivatives of diazepam.



N NH

OH OH

R

R2R

1

t - Bu

NN

CNONH

R

(3) (4)

N. Gokhan et al.64 have synthesized the pyrazoline derivatives of 1-N-substituted

thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines (5) as MAO inhibitors. Mohammad

Abid and Amir Azam65 have synthesized 1-N-substituted cyclized pyrazoline of

thiosemicarbazones (6) and reported as antiamoebic agents. V. Malhotra et al.66 have

documented new pyrazolines as a cardiovascular agents. Antidepressant activity of

pyrazoline derivatives have been reported by M. Q. Fan and coworkers.67

NN R

CH3

ClNN

S

S

NHR

1

R

(5) (6)

Abd El-Galil E. Amr et al.68 have synthesized some new 3-substituted

androstano[17,16-c]-5,2-aryl-pyrazolines and reported their antiandrogenic activity. B.

Bizzarri et al.69 have reported in vitro selective anti-helicobacter pylori activity (7) of

pyrazoline derivatives. Bhat and coworkers70 reported cytotoxic properties of pyrazoline

derivatives. Antibacterial activity of pyrazoline derivatives have been reported by A. M.

Gandhi and coworkers.71 S. Bondock et al.72 have synthesized pyrazolines as

antimicrobial agents. S. P. Hiremath et al.73 have synthesized pyrazolines as analgesic,

antiinflammatory and antimicrobial agents. Rajendra Prasad et al.74 have synthesized

some 1,3,5-triphenyl-2-pyrazolines (8) and 3-(2"-hydroxynaphthalen-1"-yl)-1,5-diphenyl-

2-pyrazolines and reported as antidepressant agents. J. H. M. Lange et al.75 synthesized

and reported 3,4-diaryl pyrazoline analogues as potent and selective CB1 cannabinoid

receptor antagonists. N. T. Ha Duong et al.76 have been synthesized some pyrazole

derivatives as inhibitors for the active sites of human liver cytochromes P450 of the 2C

subfamily.



NN

R

R1

NNR

2

R1R

(7) (8)

X. Zhang and coworkers77 have been prepared pyrazoline derivatives (9) as potent

selective androgen receptor modulators. R. M. Mohareb and coworkers78 have been

reported pyrazole derivatives (10) as a antitumor agent.

NH

N

O

NH

R6R

5

R3R

2

R1 R

4

(9)

NN

COCH2CN

NH2

X

(10)

F. Chimenti and coworkers79 have been demonstrated a novel series of 1-acetyl-3-

(4-hydroxy and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives

(11) and investigated for the ability to selectively inhibit the activity of monoamine

oxidase (MAO). Y. R. Huang et al.80 have been prepared a series of 4-alkyl-1,3,5-

triarylpyrazoles (12) as ligands for the estrogen receptor. C. D. Cox et al.81 and J. R.

Goodell et al.82 have been reported separately some pyrazoline derivatives as anti-obesity

agents by antagonizing CB1 receptors and therapeutic candidates for parkinson’s disease.

A series of 3-(4-fluorophenyl)-4,5-dihydro-N-[4-(trifluoromethyl)-phenyl]-4-[5-

(trifluoromethyl)-2-pyridyl]-1H-pyrazole-1-carboxamide has been synthesized and

studied for their potent foliar activity against both lepidoptera and orthoptera insects by P.

K. Leonard et al.83 Bruce G. Szczepankiewicz et al.84 have been prepared some pyrazole

derivatives as ant mitotic agents with activity in multi-drug resistant cell lines.

N N

R1

R2NN

O

R1

R

(11) (12)



Guniz Kuchkguzel et al.85 have synthesized pyrazolines as a antimicrobial and

anticonvulsant agents. P. Singh and coworkers86 have prepared pyrazolines as a antitumor

agent.


K. S. Nimavat87 have synthesized 1-substituted 3-aryl-5-(3’-bromophenyl)-

pyrazolines which shows anticancer, antitubercular and antimicrobial activity. D. H.

Vyas88 reported synthesis and biological activity of some pyrazoline derivatives bearing

3,5-dibromo-4-methoxybenzaldehyde nucleus.

P. T. Chovatia89 have been reported 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-

pyrazole derivatives as a antitubercular and antimicrobial agent. T. K. Dave90 reported

synthesis, antitubercular and antimicrobial evaluation of pyrazole derivatives bearing

nicotinic acid nucleus. Synthesis of some pyrazolo[3,4-d]pyrimidines and thiazolo[4,5-

d]pyrimidines and evaluation of their antimicrobial activities with derivatives of urea and

thiourea was reported by J. D. Akbari et al.91,92

Literature survey reveals that the compounds bearing pyrazole moiety possess

potential drug activity. Looking to the diversified biological activities we have

synthesized some pyrazole derivatives in order to achieving better therapeutic agents.

These studies are described in following section.

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 1H-INDOL-2-

YL[3-ARYL/THIOPHENE-5-(THIOPHEN/ARYL-2-YL)-4,5-

DIHYDRO-1H-PYRAZOL-1-YL]METHANONES.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF 1H-INDOL-2-YL[3-

ARYL/THIOPHENE-5-(THIOPHEN/ARYL-2-YL)-4,5-DIHYDRO-1H-PYRAZOL-

1-YL]METHANONES.

Pyrazole derivatives represent one of the most active class of compound having a

wide spectrum of biological activities. Looking to the interesting properties of pyrazoles

it was considered worthwhile to synthesize a series of pyrazoles for obtaining biologically

potent agent which were prepared by reacting chalcones with 1H-indole-2-

carbohydrazide in glacial acetic acid.

REACTION SCHEME

NH

NH

O

NH2

SO

R

SO

R

NH

NN

S

O

R

NH

NN

O

S

R

gla. acetic acid

gla. acetic acid




















[A] Preparation of 1H-Indole-2-carbohydrazide.

See Part-A, Part-II, Section-I, Experimental section [A].

[B] Preparation of 1-Phenyl-3-(thiophen-2-yl)prop-2-en-1-ones.

These were prepared by condensation of thiophen-2-carbaldehyde and substituted

acetophenones in the presence of sodium hydroxide as described by N. M. Rateb93 and

Dalla Via,94 M. M. Hania.95

[C] Preparation of 3-Phenyl-1-(thiophen-2-yl)prop-2-en-1-one.

These were prepared by condensation of 2-acetylthiophen and substituted aryl

aldehyde in the presence of sodium hydroxide as described by B. Ramesh et al.96

[D] General procedure for the preparation of 1H-Indol-2-yl[3-aryl/thiophene-5-

(thiophen/aryl-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.

1H-Indole-2-carbohydrazide (1.75 g, 0.01 mol) was charged into 250 ml round

bottom flask. 10 ml of glacial acetic acid was added to dissolve it. Then add substituted

chalcones (0.01 mol). The reaction mixture was refluxed on an oil bath for 12 hour. The

progress and the completion of the reaction were monitoring by TLC. After the

completion of reaction the mixture was poured onto crushed ice to give solid product.

Finally, it was purified by colum chromatography. (eluent 3 : 7 = E.A. : Hexane)

Similarly other compounds were prepared. The physical constants of the product are

recorded in Table-7a.



[E] Biological evaluation of 1H-Indol-2-yl[3-aryl/thiophene-5-(thiophen/aryl-2-

yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.





Table-7a: Physical constant of 1H-Indol-2-yl[3-aryl/thiophene-5-(thiophen/aryl-2-

yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.

NH

NN

R

R1

O

Sr. No Substitution R Substitution R1 M. F. M. W. Yield

(%) Rf

value

7a S

Cl

C22H16ClN3OS

405.89 68 0.41

7b ″ CH3

C23H19N3OS

385.48 73 0.53

7c ″

C22H17N3OS

371.45 71 0.67

7d ″ F

C22H16FN3OS

389.44 69 0.49

7e ″ Cl

Cl

C22H15Cl2N3OS

440.34 82 0.59

7f ″

NH2 C22H18N4OS

386.46 75 0.54

7g ″ NH2

C22H18N4OS

386.46 63 0.66

7h ″ N

+O

-

O C22H16N4O3S

416.45 77 0.43

7i ″ Br

C22H16BrN3OS

450.35 75 0.51

7j ″ OH

C22H17N3O2S

387.45 68 0.55

7k F

S C22H16FN3OS

389.44 81 0.47

7l

Cl

″

C22H16ClN3OS

405.89 76 0.46



7m CH3

″

C23H19N3OS

385.48 73 0.53

7n

″

C22H17N3OS

371.45 66 0.64

7o Cl

″

C22H16ClN3OS

405.89 62 0.68

7p N

+

O-

O

″

C22H16N4O3S

416.45 68 0.50

7q N+

O-

O

″

C22H16N4O3S

416.45 74 0.38

7r NH2

″

C22H18N4OS

386.46 62 0.48

7s Br

″

C22H16BrN3OS

450.35 80 0.39

7t

OCH3

″

C23H19N3O2S

401.48 79 0.59


ANALYTICAL DATA

[5-(4-Chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)

methanone (7a). mp 145-147 °C; Purity by HPLC: 94 %; IR (KBr): 3365 (N-H str), 3090

(Ar, C-H str), 2955 (C-H str), 2908 (C-H str), 1637 (amide, C=O str), 1610 (C=N str),

1556 (Ar, C=C str), 1475 (Ar, C=C str), 1184 (N-N str), 1014 (C-N str), 796 (C-Cl) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 3.20-3.26 (dd, J=3.92&17.60 Hz, 1H, CH), 3.70-

3.76 (dd, J=8.64&16.60 Hz, 1H, CH), 5.82-5.86 (dd, J=3.80&11.40 Hz, 1H, CH), 6.87-


ArH), 7.45-7.57 (m, 2H, ArH), 7.59-7.68 (m, 1H, ArH), 9.61 (s, 1H, NH). 13C NMR (100

MHz, CDCl3): δ ppm 41.97, 55.43, 115.84, 124.70, 124.83, 125.08, 126.87, 127.86,

127.95, 128.15, 128.40, 129.07, 129.31, 129.74, 130.37, 130.45, 131.10, 137.01, 159.23,

164.58; MS: m/z = 405 [M]+; Anal. Calcd for C22H16ClN3OS: C, 65.10; H, 3.97; N, 10.35.

Found: C, 65.03; H, 3.85; N, 10.21%.



1H-Indol-2-yl[5-(4-methylphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]

methanone (7b). mp 231-232 °C; Purity by HPLC: 97 %; IR (KBr): 3580, 3072, 2956,

2842, 1682, 1600, 1582, 1438, 1146, 1021, 840 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm

2.44 (s, 3H, CH3), 3.36-3.42 (dd, J=4&17.6 Hz, 1H, CH), 3.73-3.80 (dd, J=11.36&17.6

Hz, 1H, CH), 6.12-6.16 (dd, J=3.96&11.32 Hz, 1H, CH), 7.08-7.19 (m, 4H, ArH), 7.27-

7.33 (m, 4H, ArH), 7.39-7.46 (m, 1H, ArH), 7.63-7.68 (m, 1H, ArH), 7.74-7.76 (d,

J=8.16 Hz, 2H, ArH), 9.79 (s, 1H, NH). 13C NMR (100 MHz, CDCl3): δ ppm 21.64,

21.72, 41.13, 56.65, 110.44, 111.85, 120.39, 120.82, 122.63, 124.84, 124.94, 126.87,

126.91, 128.26, 128.35, 128.58, 128.65, 129.36, 129.47, 129.72, 131.97, 136.87, 141.54,

143.95, 156.00, 158.42; MS: m/z = 387 [M+2]+; Anal. Calcd for C23H19N3OS: C, 71.66;

H, 4.97; N, 10.90. Found: C, 71.49; H, 4.82; N, 10.86%.

1H-Indol-2-yl[5-phenyl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanone

(7c). mp 169-171 °C; IR (KBr): 3561, 3071, 2941, 2862, 1683, 1621, 1558, 1423, 1175,

1012 cm-1; MS: m/z = 371 [M]+; Anal. Calcd for C22H17N3OS: C, 71.14; H, 4.61; N,

11.31. Found: C, 71.02; H, 4.55; N, 11.27%.

[5-(4-Fluorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)

methanone (7d). mp 133-135 °C; IR (KBr): 3568, 3086, 2955, 2872, 1681, 1593, 1588,

1568, 1422, 1156, 1113, 820 cm-1; MS: m/z = 390 [M+1]+; Anal. Calcd for C22H16FN3OS:

C, 67.85; H, 4.14; N, 10.79. Found: C, 67.76; H, 4.10; N, 10.69%.

[5-(2,4-Dichlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-

yl)methanone (7e). mp 128-130 °C; IR (KBr): 3572, 3071, 2936, 2858, 1686, 1598,

1570, 1554, 1429, 1188, 1050, 720 cm-1; MS: m/z = 441 [M+1]+; Anal. Calcd for

C22H15Cl2N3OS: C, 60.01; H, 3.43; N, 9.54. Found: C, 59.87; H, 3.31; N, 9.42%.

[5-(3-Aminophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)

methanone (7f). mp 205-207 °C; IR (KBr): 3564, 3068, 2976, 2828, 1684, 1613, 1579,

1546, 1438, 1164, 1049, 780 cm-1; MS: m/z = 386 [M]+; Anal. Calcd for C22H18N4OS: C,

68.37; H, 4.69; N, 14.50. Found: C, 67.35; H, 4.47; N, 14.37%.


methanone (7g). mp 117-119 °C; IR (KBr): 3579, 3079, 2982, 2837, 1690, 1609, 1559,




68.37; H, 4.69; N, 14.50. Found: C, 67.89; H, 4.52; N, 14.35%.

1H-Indol-2-yl[5-(3-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]

methanone (7h). mp 123-124 °C; IR (KBr): 3548, 3062, 2979, 2842, 1689, 1606, 1576,

1568, 1434, 1164, 1024, 780 cm-1; MS: m/z = 417 [M+1]+; Anal. Calcd for C22H16N4O3S:

C, 63.45; H, 3.87; N, 13.45. Found: C, 62.35; H, 3.75; N, 13.38%.

[5-(4-Bromophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)

methanone (7i). mp 165-167 °C; IR (KBr): 3589, 3079, 2961, 2853, 1682, 1600, 1575,

1562, 1451, 1174, 1029, 855 cm-1; MS: m/z = 450 [M]+; Anal. Calcd for C22H16BrN3OS:

C, 58.67; H, 3.58; N, 9.33. Found: C, 57.82; H, 3.22; N, 9.27%.

[5-(4-Hydroxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)

methanone (7j). mp 159-161 °C; IR (KBr): 3588, 3086, 2946, 2866, 1686, 1611, 1588,

1573, 1466, 1166, 1010, 842 cm-1; MS: m/z = 388 [M]+; Anal. Calcd for C22H17N3O2S: C,

68.20; H, 4.42; N, 10.85. Found: C, 67.88; H, 4.29; N, 10.68%.

[3-(4-Fluorophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)

methanone (7k). mp 135-136 °C; IR (KBr): 3481, 3108, 2923, 2871, 1697, 1590, 1578,

1554, 1492, 1135, 1028, 830 cm-1; MS: m/z = 391 [M+1]+; Anal. Calcd for C22H16FN3OS:

C, 67.85; H, 4.14; N, 10.79. Found: C, 66.88; H, 4.07; N, 10.57%.


methanone (7l). mp 212-214 °C; IR (KBr): 3395, 3051, 2987, 2856, 1704, 1617, 1608,


C22H16ClN3OS: C, 65.10; H, 3.97; N, 10.35. Found: C, 64.87; H, 3.71; N, 10.23%.

1H-Indol-2-yl[3-(4-methylphenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]

methanone (7m). mp 187-189 °C; IR (KBr): 3371, 3108, 3005, 2915, 1689, 1584, 1578,


71.66; H, 4.97; N, 10.90. Found: C, 70.49; H, 4.73; N, 10.56%.

1H-Indol-2-yl[3-phenyl-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanone

(7n). mp 232-234 °C; IR (KBr): 3386, 3067, 2984, 2859, 1694, 1605, 1591, 1595, 1483,



1204, 1023, 845 cm-1; MS: m/z = 371 [M]+; Anal. Calcd for C22H17N3OS: C, 71.14; H,

4.61; N, 11.31. Found: C, 70.66; H, 4.28; N, 11.07%.


methanone (7o). mp 221-223 °C; IR (KBr): 3365, 3048, 2988, 2851, 1682, 1571, 1580,


C22H16ClN3OS: C, 65.10; H, 3.97; N, 10.35. Found: C, 64.59; H, 3.61; N, 10.09%.

1H-Indol-2-yl[3-(2-nitrophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]

methanone (7p). mp 213-214 °C; IR (KBr): 3486, 3152, 3046, 2846, 1676, 1651, 1612,


63.45; H, 3.87; N, 13.45. Found: C, 62.38; H, 3.53; N, 13.39%.

1H-Indol-2-yl[3-(4-nitrophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-

yl]methanone (7q). mp 188-189 °C; IR (KBr): 3386, 3089, 3018, 2914, 1689, 1586,

1579, 1523, 1469, 1087, 1028, 825 cm-1; MS: m/z = 416 [M]+; Anal. Calcd for

C22H16N4O3S: C, 63.45; H, 3.87; N, 13.45. Found: C, 62.87; H, 3.59; N, 13.19%.


methanone (7r). mp 195-197 °C; IR (KBr): 3519, 3076, 2964, 2852, 1704, 1609, 1581,


68.37; H, 4.69; N, 14.50. Found: C, 67.78; H, 4.53; N, 14.28%.

[3-(4-Bromophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)

methanone (7s). mp 173-175 °C; IR (KBr): 3312, 3128, 3064, 2883, 1683, 1615, 1586,

1542 1453, 1286, 1003, 737 cm-1; MS: m/z = 451 [M+1]+; Anal. Calcd for

C22H16BrN3OS: C, 58.67; H, 3.58; N, 9.33. Found: C, 57.63; H, 3.27; N, 9.05%.

1H-Indol-2-yl[3-(4-methoxyphenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]

methanone (7t). mp 104-106 °C; IR (KBr): 3428, 3162, 3029, 2918, 1711, 1610, 1591,


68.81; H, 4.77; N, 10.47. Found: C, 68.23; H, 4.23; N, 10.05%.




HPLC of compound 7a





Minutes0 1 2 3 4 5 6 7 8 9 10 11 12

0

200

400

600

2.17

6 1

1677

0.1

22.

421

267

14 0

.28

2.98

7 2

5028

5 2

.62

3.63

7 3

2176

0.3

4

4.41

6 9

0745

36 9

4.98

5.50

4 1

5401

9 1

.61

7.75

5 3

073

0.0

3

10.1

01 1

862

0.0

2

5007501000125015001750200025003000350040001/cm

20

40

60

80

100

%T

3365

.90

3155

.65

3090

.07

2955

.04

2908

.75

2866

.32

1637

.62

1610

.61

1581

.68

1556

.61

1475

.59

1410

.01

1344

.43

1313

.57

1274

.99

1184

.33

1138

.04

1105

.25

1072

.46

1014

.59

993.

3794

7.08

900.

7986

8.00

835.

2179

6.63

765.

7770

7.90

669.

3260

760

KAJ-PHV-1

NH

NN

O

S

Cl





NH

NN

O

S

ClM. Wt. = 405.89

NH

NN

O

S

CH3

M. Wt. = 385.48





NH

NN

O

S

Cl





NH

NN

O

S

CH3





NH

NN

O

S

Cl

NH

NN

O

S

CH3



Table-7b: Antimicrobial activity of 1H-Indol-2-yl[3-aryl/thiophene-5-(thiophen/aryl-

2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.

Sr. No.




7a 250 200 100 62.5 200 200 200 7b 500 100 100 200 250 500 250 7c 200 500 200 250 500 250 500 7d 100 200 100 200 1000 1000 1000 7e 200 250 62.5 100 200 >1000 250 7f 200 125 250 500 1000 500 500 7g 500 100 250 200 500 1000 200 7h 125 250 500 250 200 200 250 7i 100 200 200 100 250 200 250 7j 50 100 125 200 500 500 500 7k 250 200 100 250 1000 250 250 7l 100 250 250 500 500 1000 500

7m 250 200 500 200 250 500 250 7n 250 500 250 100 1000 500 >1000 7o 500 100 200 125 250 200 200 7p 250 500 100 200 200 250 500 7q 100 100 500 250 250 500 1000 7r 250 500 500 200 500 200 500 7s 100 250 200 500 >1000 200 200 7t 500 200 100 250 200 1000 500











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Part – C

(Part – II)

Studies on Pyrimidine Derivatives


Pyrimidine derivatives… 178

INTRODUCTION

Pyrimidine is the most important member of all the diazines as this ring system

occurs widely in living organisms. Purines, uric acid, barbituric acid, anti-malarial and

anti-bacterial agents also contain the pyrimidine ring. The chemistry of pyrimidine has

been widely studied. Pyrimidine was first isolated by Gabriel and Colman in 1899. Since

pyrimidine is symmetrical about the line passing C-2 and C-5, the positions C-4 and C-6

are equivalent and so N-1 and N-3 are equivalent. Depicts the five possible isomeric

structures of dihydropyrimidines, exhibiting different dispositions of the double bonds.

N

NH

NH

NH

N

NH

N

N

N

N

1,2- 1,4- 1,6- 2,5- 4,5-

A B C D E

SYNTHETIC ASPECT

Different methods have been cited to synthesize some new pyrimidines by several

coworkers using various interesting substrates.

1. N. A. Hassan et al.1 have synthesized various differently substituted

furopyrimidine moieties via different sets of reactants and varying reaction

parameters.

O

CN

NH2

R

R1

PhNCO

O

R

R1

NH

N

O

PhNH

2. Ladda and Bhatnagar2 have described an efficient nimentowski synthesis of novel

pyrimido pyrimidinones via the intermediate preparation of pyrimidin-4-one.

X

CN

NH2

R

R1

X

R

R1

N

NH

O

HCOOH

X = O/S



3. X. S. Wang3 have synthesized 5,7-diarylpyrido[2,3-d]pyrimidine derivatives using

KF-alumina catalyst.

Ar CH CH CO

Ar'N

N

OH

NH2NH2

KF/Al2O3

N

Ar

Ar'

NH

N

O

NH2

+

4. Sachin S. Laddha et al.4 have synthesized 8H-pyrido[2',3':4,5]pyrimido.

N NH2

CNR1

R2

HCOOHReflux

N

R1

R2

NH

N

O

There are several strategies to prepare fused pyrimidine ring systems. The

construction of a pyrimidine ring system from 2-amino five / six membered heterocyclic

derivatives follows the typical reaction sequence. One of the most popular approaches to

construct the pyrimidine ring is via the synthesis of substituted ureas and thio ureas. In a

first step, the amino group of the any heterocycle moiety is converted into a urea by

treatment with an isocyanate5, potassium cyanate hydrochloride6, or chlorosulfonyl

isocyanate7 and into a thiourea by reaction with an isothiocyanate8, or thiophosgene and

an amine9. The resulting ureas and thioureas readily undergo an intramolecular

cyclization upon treatment with bases or acids to afford the fused pyrimidine ring

systems.

X

H2NA

X

NH

AY

NHR

NH

AY

NR

Z

A : Hetrocycle ringX = CO2Et or CN

Y = O or S X = CN, Z = NHX = CO2Et, Z = O

The synthesis of substituted pyrimidin-4-ones is well studied and can be

categorized into four groups according to the functional groups on the fused heterocyclic

moiety and the structures of the intermediates.

(1) Substituted pyrimidinones can be prepared via cyclization of diamides

intermediates, which are generated from aminocarbamoylbenzopyrans by reaction



with acylating agents such as orthoesters,10 acid anhydrides and acid chlorides,11

formic acid12 and diethyl oxalate.13

(2) Alternatively, the synthesis of substituted pyrimidinones can be achieved from

aminoalkoxycarbonylbenzopyrans. Amidine intermediates, formed by the reaction

of the fused heterocyclic compound with amides,14 nitrites under acidic

conditions,15 orthoesters and amines,16 undergo an intramolecular cyclization to

afford chromeno pyrimidinones.

(3) A third procedure is based on the recyclization of substituted oxazinones, which

are generated by reaction of aminocarboxylic acids or esters with acid chlorides or

orthoesters.17 The recyclization proceeds through the diamide intermediate which

is generated upon treatment with amines.18

(4) Aminocyanoheterocyclic compounds also serve as valuable starting materials for

the synthesis of substituted pyrimidinones. Initially, the oxazinimine intermediates

are generated by the acylation of the amino group and then recyclization in the

presence of an acid occurs to afford substituted pyrimidinones.19

NH2

O

NH2

A1)RCOX NH2

O

NHA

R O

OR'''

O

NH2

A RCONH2 or RCN, H+ OR''

O

NA

R NH2

2)or RC(OEt)3, amine

NX

NA

O

R

A : Hitrocyclic ringX = H or R'

OR'''

O

NH2

A3) RCOCl or RC(OEt)3 O

NA

O

R

NH2

O

NH2

A4) RCOCl or (RCO)2OH+

O

NA

NH

R

NX

NA

O

R

A : Hetrocyclic ringX = H or R'

R''' = H or alkyl

R'NH2





been encountered with several pyrimidines such as,

1. Antibacterial20

2. Antitumor21


4. Cytotoxic activity23

5. Antimalarial24

6. Antiproliferation25

7. Antiparasitic26

8. Antifungal27

9. Anticancer28

10. Antineoplastics29

Alloxan (1) is known for its diabetogenic action in a number of animals30 Uracil

(2), thymine (3) and cytisine (4) are the three important constituents of nucleic acids.

NH

NH

O O

OO

NH

NH

O

O

NH

NH

O

O

N

NH

O

NH2

(1) Alloxan (2) Uracili (3) Thymine (4) Cytisine

Calcium ion plays a vital role in a large number of cellular processes, including

excitation-contraction and stimulus-secretion.31,32 The regulation of the intracellular

concentration of this ion makes possible the control of such Ca2+ dependent processes.

One means of accomplishing this is by the use of agents known as calcium channel

antagonists, which inhibit the movement of calcium through certain membrane channel.33-

35 K. S. Atwal36 prepared the 2-heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5-

pyrimidinecarboxylic acid esters (5), which lack the potential C3 symmetry of

dihydropyridine calcium channel blockers. The solid-state structure of dihydropyrimidine

analogue (6) shows that these compounds can adopt a molecular conformation which is

similar to the reported conformation of dihydropyridine calcium channel blockers.



NH

NCOOR

3

R2X

R1

NH

NCOOEt

S

NO2

(5) (6)

S. Sarac and coworkers37,38 have synthesized 4-arlyl-3,4-dihydropyrimidin-2(1H)-

one/thione derivatives. The calcium channel blocker activities of all compounds

performed on isolated rat ileum. Product (7), 2-nitrophenyl derivative and (8), 2-

bromophenyl derivative have potent antispasmodic activity on BaCl2 stimulated rat ileum.

NH

NH

SH5C2

NO2H3COOC

(7)

NH

NH

OCH3

BrO

CH3

(8)

N. Dhanapalan and coworkers39 have synthesized dihydropyrimidinones and

describe compound (9) have a high binding affinity (Ki = 0.2nM) for a1a receptor and

greater than 1500 fold selectivity over a1b and a1d adrenoceptors.

N

NH

CH3

O

CH3

FF

O

NH

O

N

COOMePh

(9)

2-Thiouracil (10c) and its alkyl analogue, thiobarbital (10e) are effective drugs

against hyperthyroidism. Propylthiouracil (10d) is used as a drug for hyperthyroidism

with minimum side effects.40



NH

NH

O

X

RR1

R2

(9c-e)(10c) = R = R1 = R2 = H, X = S, 2-Thiouracil

(10d) = R = R1 = H, R2 = C3H7, X = S, Propylthiouracil

(10e) = R = R1 = C2H5, R2 = O, X = S, Thiobarbital

These drugs have the ability of ridding the body of parasitic worms. Pyrantel

pamoate (11) is a depolarizing neuromuscular blocking agent that causes spastic paralysis

in helminthes and is employed in the treatment of infestations caused by pinworms and

roundworms.41

(11) Pyrantel pamoate

N

NSCH3


P. D. Zalavadiya42 have synthesized some new dihydropyrimidines by iodine

catalyst at ambient temperature and reported as antitubercular agent. Pyrazolo[3,4-d]

pyrimidines and thiazolo[4,5-d]pyrimidines reported by J. D. Akbari et al.43 Green

chemistry approach to synthesis of some new trifluoromethyl containing

tetrahydropyrimidines was reported by H. S. Joshi et al.44



under taken the synthesis of several pyrido[2,3-d]pyrimidin which has been described

as under.

SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-METHYL

-5-ARYL/THIOPHEN-7-(THIOPHEN/ARYL-2-YL)PYRIDO[2,3-

d]PYRIMIDIN-4(3H)-ONES.



SECTION-I

SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-METHYL-5-

ARYL/THIOPHEN-7-(THIOPHEN/ARYL-2-YL) PYRIDO[2,3-d]PYRIMIDIN -

4(3H)-ONES.

Much interest has been focused around pyrido[2,3-d]pyrimidines derivatives

because of their wide variety of pharmacological properties and industrial application. In

view of these finding and achieve to better drug potency, we have synthesized 2-Methyl-

5-aryl/thiophen-7-(thiophen/aryl-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-ones by the

cyclocondensation of 2-amino-6-aryl/thiophene-4-(thiophene/aryl-2-yl)pyridine-3-

carbonitrile with glacial acetic acid.

REACTION SCHEME

SO

R

SO

R

N S

N

NH2

R

N

SN

NH2 R

N

NH

N S

O

CH3

R

N

S

NH

N

O

CH3 R

MeOH

MeOH

Malanonitrile

Malanonitrile

gla. acetic acid

gla. acetic acid

Reflux

Reflux
















on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in DMSO-d6 solution on a Bruker Ac 400 MHz spectrometer.




[A] Preparation of 1-Aryl/thiophen-3-(thiophen/aryl-2-yl)prop-2-en-1-one.

See Part-C, Part-I, Section-I, Experimental section [B] and [C].

[B] Preparation of 2-Methyl-4-aryl/thiophen-6-(thiophen/aryl-2-yl)pyridine-3-

carbonitrile.45

A mixture of chalcone (0.01 mol), malononitrile (0.66 g, 0.01 mol) and

ammonium acetate (6.16 g, 0.08 mol) in a methanol (20 ml) was refluxed for 4-6 hour.

After the completion of reaction (monitoring by TLC), cool the content, the solid

separated was filtered and wash with methanol and dried to give analytical pure product.

[C] General procedure for the preparation of 2-Methyl-5-aryl/thiophen-7-

(thiophen/aryl-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-ones.

A mixture of an appropriate 2-methyl-4-aryl/thiophen-6-(thiophen/aryl-2-yl)

pyridine-3-carbonitrile (0.01 mol) and acetic acid (20 ml) was stirred under reflux for 12-

14 hour in the presence of catalytic amount of concentrated H2SO4. The reaction mixture

was allowed to cool to room temperature and was poured into ice cold water. The solid

thus formed was collected by filtration, washed with chloroform (20 ml) and the resulting

crude product was crystallized from methanol to give the analytical pure compound. The

physical constants of the product are recorded in Table-8a.

[D] Biological evaluation of 2-Methyl-5-aryl/thiophen-7-(thiophen/aryl-2-yl)

pyrido[2,3-d]pyrimidin-4(3H)-ones.





Table-8a: Physical constant of 2-Methyl-5-aryl/thiophen-7-(thiophen/aryl-2-yl)


N

R

NH

N R1

O

CH3

Sr. No Substitution R Substitution R1 M. F. M. W. Yield

(%) Rf

value

8a S

Cl C18H12ClN3OS 353.82 75 0.36

8b ″ CH3 C19H15N3OS 333.40 82 0.48

8c ″ C18H13N3OS 319.38 69 0.41

8d ″ F C18H12FN3OS 337.37 73 0.37

8e ″ Cl

Cl

C18H11Cl2N3OS

388.27

71 0.51

8f ″

NH2 C18H14N4OS

334.39

63 0.46

8g ″ NH2

C18H14N4OS

334.39

65 0.52

8h ″ N

+O

-

O C18H12N4O3S

364.37

78 0.59

8i ″ Br

C18H12BrN3OS

398.27

77 0.63

8j ″ OH

C18H13N3O2S

335.37

81 0.33

8k F

S C18H12FN3OS

337.37

83 0.57

8l

Cl

″ C18H12ClN3OS 353.82 78 0.50

8m CH3

″

C19H15N3OS

333.40

76 0.47



8n

″

C18H13N3OS

319.38

70 0.60

8o Cl

″

C18H12ClN3OS

353.82

69 0.63

8p N

+

O-

O

″

C18H12N4O3S

364.37

72 0.62

8q N+

O-

O

″

C18H12N4O3S

364.37

74 0.58

8r NH2

″

C18H14N4OS

334.39

65 0.40

8s Br

″

C18H12BrN3OS

398.27

68 0.53

8t

OCH3

″

C19H15N3O2S

349.40

71 0.42

TLC solvent system:- MeOH : CHCl3 = 1 : 9

ANALYTICAL DATA

7-(4-Chlorophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8a). mp 179-181 °C; Purity by HPLC: 95 %; IR (KBr): 3390 (N-H str), 3028 (Ar, C-H

str), 2935 (C-H str), 2853 (C-H str), 1687 (amide, C=O str), 1611 (C=N str), 1532 (Ar,

C=C str), 1446 (Ar, C=C str), 1015 (C-N str), 820 (C-H, o.p. ban) cm-1; 1H NMR (400

MHz, DMSO-d6): δ ppm 2.51 (s, 3H, CH3), 7.29-7.31 (m, 1H, ArH), 7.46-7.49 (m, 1H,

ArH), 7.59-7.60 (d, J=4.4 Hz, 1H, ArH), 7.69-7.70 (d, J=5.20 Hz, 2H, ArH), 7.83-7.84

(d, J=4.40 Hz, 2H, ArH), 7.98 (s, 1H, NH), 8.18-8.20 (d, J=9.08 Hz, 1H, ArH). 13C NMR

(100 MHz, DMSO-d6): δ ppm 21.08, 111.23, 112.70, 114.62, 117.92, 123.23, 124.00,

128.80, 130.20, 132.10, 135.45, 139.12, 141.14, 154.16, 159.78, 165.18; MS: m/z = 355

[M+1]+; Anal. Calcd for C18H12ClN3OS: C, 61.10; H, 3.42; N, 11.88. Found: C, 60.31; H,

3.27; N, 11.65%.

2-Methyl-7-(4-methylphenyl)-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8b). mp 186-188 °C; Purity by HPLC: 96 %; IR (KBr): 3365, 3068, 2979, 2851, 1694,

1611, 1571, 1567, 1456, 1078, 840 cm-1; 1H NMR (400 MHz, DMSO-d6): δ ppm 2.44 (s,



3H, CH3), 2.79 (s, 3H, CH3), 7.16-7.18 (m, 1H, ArH), 7.33-7.37 (m, 1H, ArH), 7.46-7.47

(d, J=2.92 Hz, 1H, ArH), 7.59-7.62 (d, J=4.64 Hz, 2H, ArH), 7.74-7.75 (d, J=3.88 Hz,

1H, ArH), 7.88 (s, 1H, NH), 8.05-8.07 (d, J=8.20 Hz, 2H, ArH). 13C NMR (100 MHz,

DMSO-d6): δ ppm 19.96, 21.03, 110.20, 117.72, 121.10, 123.45, 127.02, 127.41, 129.40,

130.28, 131.78, 135.20, 138.64, 141.76, 153.20, 158.21, 163.28; MS: m/z = 334 [M+1]+;

Anal. Calcd for C19H15N3OS: C, 68.45; H, 4.53; N, 12.60. Found: C, 68.07; H, 4.41; N,

12.29%.

2-Methyl-7-phenyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8c). mp 141-

142 °C; IR (KBr): 3433, 3078, 2976, 2858, 1692, 1612, 1569, 1567, 1443, 1013 cm-1;

MS: m/z = 319 [M]+; Anal. Calcd for C18H13N3OS: C, 67.69; H, 4.10; N, 13.16. Found: C,

66.38; H, 4.04; N, 13.00%.

7-(4-Fluorophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8d). mp 159-161 °C; IR (KBr): 3459, 3086, 2966, 2846, 1693, 1611, 1572, 1564, 1450,

1061, 825 cm-1; MS: m/z = 339 [M+2]+; Anal. Calcd for C18H12FN3OS: C, 64.08; H, 3.59;

N, 12.46. Found: C, 63.66; H, 3.49; N, 12.34%.

7-(2,4-Dichlorophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8e). mp 239-241 °C; IR (KBr): 3464, 3068, 2969, 2884, 1693, 1613, 1586, 1570, 1454,

1029, 747 cm-1; MS: m/z = 389 [M+1]+; Anal. Calcd for C18H11Cl2N3OS: C, 55.68; H,

2.86; N, 10.82. Found: C, 55.13; H, 2.48; N, 10.72%.

7-(3-Aminophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8f). mp 167-169 °C; IR (KBr): 3497, 3068, 2946, 2860, 1697, 1609, 1576, 1568, 1446,

1007, 759 cm-1; MS: m/z = 334 [M]+; Anal. Calcd for C18H14N4OS: C, 64.65; H, 4.22; N,

16.75. Found: C, 64.31; H, 4.10; N, 16.35%.


(8g). mp 118-120 °C; IR (KBr): 3455, 3055, 2968, 2835, 1691, 1618, 1561, 1569, 1453,


16.75. Found: C, 64.18; H, 4.08; N, 16.43%.

2-Methyl-7-(3-nitrophenyl)-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8h).

mp 243-245 °C; IR (KBr): 3500, 3097, 2976, 2849, 1695, 1600, 1565, 1562, 1435, 1071,



738 cm-1; MS: m/z = 365 [M+1]+; Anal. Calcd for C18H12N4O3S: C, 59.33; H, 3.32; N,

15.38. Found: C, 58.91; H, 3.13; N, 15.06%.

7-(4-Bromophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8i). mp 144-146 °C; IR (KBr): 3468, 3079, 2991, 2864, 1690, 1605, 1573, 1565, 1459,

1034, 690 cm-1; MS: m/z = 399 [M]+; Anal. Calcd for C18H12BrN3OS: C, 54.28; H, 3.04;

N, 10.55. Found: C, 53.65; H, 2.84; N, 10.36%.

7-(4-Hydroxyphenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8j). mp 188-189 °C; IR (KBr): 3488, 3086, 2946, 2868, 1697, 1612, 1581, 1580, 1456,

1022, 857 cm-1; MS: m/z = 335 [M]+; Anal. Calcd for C18H13N3O2S: C, 64.46; H, 3.91; N,

12.53. Found: C, 63.54; H, 3.77; N, 12.31%.

5-(4-Fluorophenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8k). mp 201-203 °C; IR (KBr): 3364, 3060, 3045, 2891, 1693, 1585, 1558, 1545, 1463,

1075, 851 cm-1; MS: m/z = 338 [M+1]+; Anal. Calcd for C18H12FN3OS: C, 64.08; H, 3.59;

N, 12.46. Found: C, 63.18; H, 3.41; N, 12.26%.


(8l). mp 256-258 °C; IR (KBr): 3468, 3051, 3008, 2960, 1698, 1618, 1604, 1578, 1471,

1078, 770 cm-1; MS: m/z = 355 [M]+; Anal. Calcd for C18H12ClN3OS: C, 61.10; H, 3.42;

N, 11.88. Found: C, 60.58; H, 3.17; N, 11.53%.

2-Methyl-5-(4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8m). mp 294-296 °C; IR (KBr): 3504, 3145, 2978, 2861, 1712, 1645, 1618, 1563, 1545,


12.60. Found: C, 67.57; H, 4.30; N, 12.49%.

2-Methyl-5-phenyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8n). mp 216-

217 °C; IR (KBr): 3341, 3029, 2983, 2866, 1709, 1595, 1583, 1568, 1478, 1018 cm-1;

MS: m/z = 319 [M]+; Anal. Calcd for C18H13N3OS: C, 67.69; H, 4.10; N, 13.16. Found: C,

67.09; H, 3.97; N, 13.05%.


(8o). mp 176-177 °C; IR (KBr): 3309, 3151, 2998, 2905, 1691, 1683, 1578, 1543, 1518,



1023, 854 cm-1; MS: m/z = 354 [M+1]+; Anal. Calcd for C18H12ClN3OS: C, 61.10; H,

3.42; N, 11.88. Found: C, 60.48; H, 3.21; N, 11.49%.

2-Methyl-5-(2-nitrophenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8p).

mp 181-183 °C; IR (KBr): 3290, 3043, 3023, 2818, 1890, 1609, 1590, 1579, 1449, 1065,

720 cm-1; MS: m/z = 364 [M]+; Anal. Calcd for C18H12N4O3S: C, 59.33; H, 3.32; N,

15.38. Found: C, 58.86; H, 3.18; N, 15.09%.

2-Methyl-5-(4-nitrophenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8q).

mp 166-167 °C; IR (KBr): 3351, 3031, 3015, 2957, 1876, 1602, 1589, 1578, 1479, 1043,

710 cm-1; MS: m/z = 364 [M]+; Anal. Calcd for C18H12N4O3S: C, 59.33; H, 3.32; N,

15.38. Found: C, 56.87; H, 3.15; N, 15.27%.


(8r). mp 210-211 °C; IR (KBr): 3481, 3147, 2969, 2884, 1707, 1578, 1563, 1533, 1469,


16.75. Found: C, 64.01; H, 4.16; N, 16.58%.

5-(4-Bromophenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8s). mp 248-250 °C; IR (KBr): 3501, 3170, 3046, 2930, 1681, 1619, 1615, 1578, 1503,

1056, 866 cm-1; MS: m/z = 399 [M+1]+; Anal. Calcd for C18H12BrN3OS: C, 54.28; H,

3.04; N, 10.55. Found: C, 53.81; H, 2.91; N, 10.41%.

5-(3-Methoxyphenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one

(8t). mp 229-230 °C; IR (KBr): 3349, 3093, 29636, 2847, 1680, 1620, 1595, 1583, 1493,

1037, 767 cm-1; MS: m/z = 349 [M]+; Anal. Calcd for C19H15N3O2S: C, 65.31; H, 4.33; N,

12.03. Found: C, 64.72; H, 4.23; N, 11.87%.




HPLC of compound 8a





Minutes0 1 2 3 4 5 6 7 8 9 10

mA

U

0

250

500

750

0.17

1 2

87 0

.00

0.64

0 1

963

0.0

2

1.90

9 9

0223

71 9

5.60

3.27

5 3

9743

5 4

.21

3.62

7 1

3653

0.1

4

4.05

3 1

747

0.0

2

4.39

5 4

39 0

.00

5007501000125015001750200025003000350040001/cm

0

20

40

60

80

100

%T

3390

.97

3243

.41

3028

.34

2935

.76 28

53.7

8

1687

.77

1611

.58

1532

.50 14

46.6

613

64.6

813

30.9

312

75.9

5

1166

.97 11

10.0

710

15.5

698

7.59 86

3.17 70

6.93

644.

25

556.

48

JP-302

N

NH

N

O

CH3

S

Cl





N

NH

N

O

CH3

S

CH3M. Wt. = 333.40

N

NH

N

O

CH3

S

ClM. Wt. = 353.82





N

NH

N

O

CH3

S

Cl





N

NH

N

O

CH3

S

CH3





N

NH

N

O

CH3

S

Cl

N

NH

N

O

CH3

S

CH3



Table-8b: Antimicrobial activity of 2-Methyl-5-aryl/thiophen-7-(thiophen/aryl-2-yl)


Sr. No.




8a 50 500 250 100 500 250 250 8b 100 250 100 250 1000 200 500 8c 125 62.5 100 200 250 500 >1000 8d 250 200 500 200 200 1000 500 8e 500 100 200 250 1000 500 1000 8f 200 100 500 200 500 >1000 500 8g 200 100 250 100 200 250 250 8h 100 200 200 250 500 200 500 8i 250 200 250 200 500 500 200 8j 500 250 500 500 >1000 500 500 8k 200 500 62.5 100 500 200 250 8l 250 100 100 500 1000 200 500

8m 100 200 500 250 500 250 500 8n 500 125 500 200 250 500 1000 8o 250 100 100 200 200 500 500 8p 200 250 200 250 >1000 >1000 500 8q 500 250 250 200 500 200 250 8r 500 200 100 250 200 250 500 8s 200 250 250 200 250 500 200 8t 200 100 500 100 250 500 200











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Publication


Publication… 199

LIST OF PUBLICATION

D. H. Purohit, B. L. Dodiya, R. M. Ghetiya, P. B. Vekariya and H. S. Joshi*

Synthesis and antimicrobial activity of some new 1,3,4-thiadiazoles and 1,3,4-

thiadiazines containing 1,2,4 triazolo nucleus, Acta chemica slovenica, 58, 53-59,

2011.

K. M. Thaker, B. L. Dodiya, K. A. Joshi, R. M. Ghetiya, P. B. Vekariya & H. S.

Joshi*, Synthesis and antimicrobial activity of some new aryl amide and

dihydroquinoline derivatives containing benzo[b]thiophene nucleus, Indian journal

of heterocyclic chemistry, 20, 21-24, 2010.

S. M. Dave, V. R. Ram, G. J. Kher, B. L. Dodiya, H. S. Joshi* Synthesis and

Spectrophotometric studies of Ni (II)-HMCPP complex and their use as an analytical

reagent, Analytical chemistry: An Indian Journal, 8(4), 430-435, 2009.

K. M. Thaker, R. M. Ghetiya, S. D. Tala, B. L. Dodiya, K. A. Joshi, K. L. Dubal &

H. S. Joshi*, Synthesis of oxadiazoles and pyrazolones nucleus as antimycobacterial

and antimicrobial agents, Indian Journal of Chemistry, Section B: Organic

Chemistry Including Medicinal Chemistry, Accepted article [MS No. SCCB-1351

Dt. 03/07/09].

P. D. Zalavadiya, R. M. Ghetiya, B. L. Dodiya, P. B. Vekariya and H. S. Joshi*

Synthesis of some new dihydropyrimidines by iodine as a catalyst at ambient

temperature and evaluation of their biological activity, journal of heterocyclic

chemistry, Accepted article [MS No. JHET-10-0340].

M. J. Joshi, P. B. Vekariya, B. L. Dodiya, R. M. Ghetiya and H. S. Joshi*

Synthesis and biological study of some new chalcones and oxopyrimidines

containing imidazo[1,2-a]pyridine nucleus, journal of heterocyclic chemistry,

Accepted article [MS No. JHET-10-0513].

M. R. Patel, B. L. Dodiya, R. M. Ghetiya, K. A. Joshi, P. B. Vekariya, A. H.

Bapodara and H. S. Joshi* Synthesis, Antitubercular and Antimicrobial Biological

Evaluation of Pyrazoline derivatives, International journal of chemtech research,

(Accepted article).

[etheses.saurashtrauniversity.edu]etheses.saurashtrauniversity.edu/534/1/dodiya_bl_thesis... · 2012-06-03 · Gram: UNIVERSITY Phone: (R) 0281-2584221 Fax: 0281-2577633 (O) 0281-2578512

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