Rabia Mushtaq - Pakistan Research Repository

Organoantimony(III/V) as Prospective

Antileishmanial and Anticancer Drugs: Synthesis and Characterization

Islamabad

A dissertation submitted to the Department of Chemistry, Quaid-i-Azam

University, Islamabad, in partial fulfilment of the requirements for the degree

of

Doctor of Philosophy

In

Inorganic/Analytical Chemistry

By

Rabia Mushtaq Department of Chemistry

Quaid-i-Azam University Islamabad

2018

CONTENTS

Acknowledgements III

Abstract V

Chapter -1 Introduction 1-27

1.1 Organometallics 2

1.2 Antimony(V) Complexes 3

1.2.1 Pentavalent Antimonials With Oxygen Donor Ligands 5

1.2.2 Pentavalent Antimonials With Carbohydrates as Ligands 7

1.2.3 Pentavalent Antimonials With Nucleosides as Ligands 7

1.2.4 Pentavalent Antimonials With Porphyrins as Ligands 8

1.2.5 Pentavalent Antimonials With Dioxygen as Bridging Ligands 8

1.3 Antimonials As Drugs: Merits and Demerits 9

1.4 Biological applications of antimony (V) complexes 11

1.5 Some Important Antimony Based Therapeutic drugs 11

1.6 Structure Activity Relationship 16

1.7 Aims and Objectives 17

1.8 Plan of Work 18

1.8.1 Choice of Ligands 18

1.8.2 Choice of Metal and Targets for Biological Studies 19

References 20 Chapter -2 Experimental and Characterization 28-53

2.1 Chemicals and Reagents 28

2.2 Software and Instrumentation 28

2.3 General Methodology for Synthesis 29

2.3.1 Synthesis of Organo-antimony (III) (a-g) & (V) (A-G) Precursors 29

2.3.2 Synthesis of Triphenylantimony(V) Dicarboxylates (1A-18A) 30

2.3.2.1 Synthesis and Characterization (1A-18A) 31

2.3.3 Synthesis of Tris(p-tolyl)antimony(V) dicarboxylates (1B-10B) 38

2.3.3.1 Synthesis and characterization data of (1B-10B) 38

2.3.4 Synthesis of Tris(2,5-dimethylphenyl) antimony(V) Dicarboxylates 43

(1C-20C)

2.3.4.1 Synthesis and characterization data of (1C-20C) 43

2.3.5 Synthesis of Organoantimony(V) Dicarboxylates (1D-10D), (1E-

52

10E), (1F-10F) and (1G-10G).

References 53

Chapter -3 Biological Studies 54-68

3.1 Biological Screening of Some Selected Pentavalent Antimonials 54

3.1.1 Antileishmanial Screening 54

3.1.2 Anti-promastigotes assays on (1A-9A) 56

3.1.3 Anti-promastigotes and anti-amastigotes assays on 10A-18A 57

(labelled in graphs as 1-9) and their parent acids (L1-L9)

3.1.4 Anti-promastigotes and Cytotoxicity assays on (1B-8B) and (1C- 60

20C)

3.1.5 Cell Viability Assay Cell Culture 64

3.1.6 In vitro Cytotoxicity Screenings of Pentavalent Antimonials (1C- 65

20C)

References 67

Chapter -4 Results and Discussion 69-99

4.1 Infrared Spectroscopy 69

4.2 1H and 13C NMR Spectroscopy 74

4.3 Single Crystal XRD Analysis 75

4.3.1 Crystal Structures of Bis(2-aminobenzoato)(triphenyl)antimony(V) 75

(1A) and Bis(3,5-dichlorobenzoato)(triphenyl)antimony (V) (4A)

4.3.2 Crystal Structures of Compounds (10A), (11A), (13A), (14A) and 81

(17A).CHCl3

4.3.3 Crystal Structures of Bis(4-methylbenzoato)tris(p-tolyl)antimony(V) 87

(1B), Bis(3,5-dichlorobenzoato)tris(p-tolyl)antimony(V) (3B) and

Bis(nicotinato)tris(p-tolyl)antimony(V) (5B)

References 96

List of Publications 98

ACKNOWLEDGEMENTS

All praises be to Almighty Allah, who is the most gracious, the most

compassionate and the kindest. Peace and blessing of Allah be upon the Holy

Prophet Muhammad (PBUH) and his pious progeny, who is the source of

knowledge and guidance for the entire human beings forever.

I am grateful to my supervisor and chairman, Prof. Dr. Amin Badshah,

Department of Chemistry, Quaid-i-Azam University, Islamabad, for his guidance,

invigorating encouragement and for providing all the necessary research facilities

throughout my research work.

A special word of thanks is due to my Co-supervisor Dr. Muhammad

Khawar Rauf, Director, Office of Research, Innovation and Commercialization,

Quaid-i-Azam University, Islamabad, for his help to carry out this research work

and valuable discussions received for Spectroscopic, Single Crystal X-Ray

Diffraction analysis and regarding biological studies. Without his generous help, the

timely completion of the work would have not been possible for me.

My cordial thanks and gratitude are due to my parents and My Husband Mr. M.

Tariq Bashir. It was their love and care that has brought me to this stage. Without

their encouragement, excessive generosity and patience, I would have not been able

to complete this task.

I am thankful to all of my friends Faiza, Saira, Shumaila and colleagues

at Quaid-i-Azam University, Islamabad. Special thanks are owned as well to my

laboratory fellows for the conversations we shared, both creative and hilarious. I am

also grateful to all supporting staff in the Department of Chemistry for the nice

cooperation.

Rabia Mushtaq

ABSTRACT

A variety of pentavalent antimonials have been synthesized from the triorganoantimony(V)

halides and a variety of carboxylic acids having known biological applications to better

understand the medicinal potential of the synthesized assemblies. The successful synthesis

of complexes 1A-18A, 1B-10B and 1C-20C was confirmed by melting points, elemental

analysis, FTIR, 1H & 13C NMR spectroscopy. The selected finely crystallized complexes

have also been analysized through single crystal X-ray diffraction technique. The

crystallographic analysis reveals that these complexes are mononuclear in solution as well

as in solid state. The carboxylate ligands bind to the antimony(V) atom through oxygen

atoms and occupy axial position adopting geometries between distorted trigonal

bipyramidal and square pyramidal. Main purpose objective of this study was to investigate

anti-leishmanial and cytotoxic/anticancer potential of the synthesized pentavalent

antimonials bearing carboxylic acids with a variety of pharmacophores. The activity of these

compounds was tested against Leishmanial tropica and human cell lines carcinomas A498

(renal), EVSA-T (breast), H226 (lung), IGROV (ovarian), M19 (melanoma-skin), MCF-7

(breast), WIDR (colon) and MDA-MB-231 and HeLa. Results of biological activities

including anti leishmanial and anti-cancer activity demonstrated that the compounds under

studies significantly inhibit Leishmania parasite and also showed promising anti-cancer

activity. The carboxylic acids showed no considerable results, while p-tolyl (1B-10B) and

2,5-dimethylphenyl (1C-20C) moieties bearing complexes exhibited potent activity

compared to the simple phenyl derivatives (1A-18A). The studies also reveal that these

compounds have considerable shelflife, reproducibility and stability in solution mediums as

used for testing of biological activities. Hence, it is suggested that reported pentavalent

antimonials, particularly with p-tolyl and 2,5-dimethylphenyl groups seem to be a safe,

reasonable and worthwhile option for the further investigations to hunt the lead therapeutic

agents for leishmaniasis and cancer.

a

IN THE NAME OF ALLAH

THE COMPASSIONATE

THE MERCIFUL

b

“Allah will exalt those who believe among you, and

those have knowledge to high ranks”

(Al-Quran)

c

Sayings of Holy Prophet (S.A.W.)

“The seeking of knowledge is obligatory for every

Muslim”

(Al-Tirmidhi)

d

Dedicated to

My Loving Parents

1

Chapter-1

INTRODUCTION

The metal-organic compounds have been used for the treatement of various diseases

for many years. In the ancient periods of civilizations, the Egyptians used copper to

make germ-free water, gold products as medicine by Arabs, in China and the use of

silver metal as well as in its chelated forms is also in practices for the pathogenic

purification of water in the modern era. The introduction of inorganic compounds as

drugs was based on the pre- and post therapy conditions. Fromthe earliest inorganic

remedies, the inorganicsaltswere used as diuretics and iron compouds as dietary

supplements. Currently, many of the gold compounds were used as anti-bacterial,

anti-tuberculosis, as anti-arthritis and anti-rheumatoid drugs. Arsenic compound

(arsephenamine) have been used as to treat syphilis [1], Bismuth subsalicylateto treat

diahrrea in children [2] and antimony complexes for the treatment of parasiticand

protozoaldiseases [3], affecting more than 50 million persons per year. In this research

assignment, we have focused on the synthesis of pentavalent antimonials solely to

find out their potential as prospective antileishmanial drugs, and additionally for their

scope as anticancer and antidiabetes mellitus drugs. In continuation of the

introductory paragraph of this chapter, it is worth mentioning that the toxicity and the

therapeutic potential of organometallics have been well studied now a day. The

appearance of metalloenzymes in the human body is widespread and included iron in

transferrin and hemoglobin, zinc in carbonic anhydrase, molybdenum in xanthine

oxidase, copper in hepatocuprein and vanadium in hemovanadin. The use

oforganometallic drugs are very common now. Few examples take account of

merbromine and meralein as an anti-septic, silver complex of sulfadiazine for burns,

arsphenamine as antimalarial, carbarsone for parasitic ailments, and

dimercaptosuccinate antimony for the treatement of schistosomiasis [4].

2

1.1. Organometallics

The first organometallic compound was prepared by Danish chemist W. C. Zeise, in

1827 by the reaction of ethanol with a mixture of PtCl2 and PtCl4 in the presence of

KCl. This was about the time as the first successful synthesis of urea in 1828 by

Wohler and about the 40 years prior to the proposal of the Periodic Table by A. D.

Mendeleev in 1869. The compound prepared and formulated as PtCl2

(C2H4).KCl.H2O by Zeise [5]. Compound with organic groups bonded to metal

through hetero atom such as O, N and S should not be called organometallic

compound even though these compounds appear to be organometallic like metal

alkoxides, metal ß-diketones, metal thiocarbonate and thiocarbamate and amine

derivatives.

There are a lot of compounds in which carbon is bonded to another nonmetallic

carbon, oxygen, nitrogen, sulfur, halogens and hydrogen but all such type of

compounds are called organic compound are studied separately, such types of

compounds are generally very stable. This stability is due to several reason one of

them is very small electronegativity of carbon and the above elements. Compounds

in which carbon is directly bonded with metal atom are generally less stable and are

prepared under inert atmosphere at low temperature. In present, the Grinard reagents

are a very popular class of organometallics used for the derivation of other

organometallics and organic compounds.

Grignard reagentsare prepared by the reaction of alkyl halides with magnesium in

the presence of ether/THF under inert manipulations.

R and Ar are alkyl and aryl group respectively. In Grignard reagent carbon which is

attached to the magnesium atom directly, is nucleophilic in nature because the

electronegativity of carbon (2.5) is greater than magnesium (1.30) and the shared pair

3

of electron is attracted towards the carbon atom of alkyl or aryl group so this group

is capable of attacking on any electrophilic center. Grignard reagent is very reactive

compound and readily decomposed. But in ether it is stabilized as a tetrahedral

complex in two donors are solvent molecules, because ether molecules have and

unpaired electron present on oxygen atom are donated to RMgX and stabilizes it.

Where ‘S’ stands for solvent molecule. But in solution the following structures have

been proposed for Grignard reagents which are in dynamic equilibrium. Grignard

reagent was extensively used in synthetic chemistry [6].

1.2. Antimony(V) Complexes

The inorganic chemistry of antimony has been a subject of scientific interests. There

is a variety of versatile organic ligands for the preparation of metal-organic

compounds with a variety of metals and non-metals like Sn, Ge, Bi, Sb and As etc.

Organometal compounds have many advantages on the drugs purely of organic

nature in medicinal chemistry. The coordination of an organic molecule, preferably

bearing some pharmacophoric groups may change the metabolic path and helps to

the controled release and prolonged availability of the drug to the target centre i.e.,

the role of metal complexes as pro-drugs can not be over ruled. Although, there are

4

many serious objections over the toxicity of heavy metal-based drugs therapies but

the significance of metal-based medicines is undisputed as depicted by their

successful use as anti-protozoal, anti-ulcer, anti-arthritis, anti-malarial, anti-cancer

and santi-microbial drugs and for the treatment of various other diseases.

Potassium salt of antimony tartrate (I) was widely used for the treatement of

parasitic and cancerious diseases near 1900, despite of their toxic nature. Now a day,

many of the antimony complexes have been reported and known for their significant

anticancer activities [7, 8].

(I)

The use of antimonials as drugs has attracted a great attention as anti-protozoal drugs,

especially, for the treatment of leishmaniasis [9-12]. Leishmaniasis is a parasite

disease caused by sand-flies into mammals and is expressed as cutaneous and visceral

ulcerious lesions [13]. The antimony(V) drugs, Pentostam (sodium salt of

stibogluconate) (II) and Glucantine (meglumine antimonite) (III) are clinically used

as front line drugs for leishmaniasis. Recent studies revealed that antimony(V) is

transformed to antimony (III) in the biological system [14]. The exact molecular

structures pentostam and glucantine drugs are still not known.

5

(II) (III)

Keeping in view the medicinal importance of antimony compounds, here we are of

the interest to synthesis a number of antimony (V) compounds with ligands having

donor atoms like O, N, and S etc. Before proceeding to the synthesis of the

compounds of our interest, we wish to give a brief review of the research work carried

out in the recent years.

1.2.1. Pentavalent Antimonials With Oxygen Donor Ligands

The carboxylic acids are the ligands which have been extensively used for the

development of metal-organic assemblies and reported in the recent years. Among the

p-block elements, derivatives of organotin and antimony precursors with carboxylic

acidshave been studied in detail. Structural diversity revealed by these metal

carboxylates is remarkable which ranges from discrete molecules to macromolecules

[15]. Compounds having carboxylic group in their functionality may act as multi-

dentate ligands and may serve as an insertion site between metal and other auxillary

species [16].

A series of phenylacetic acids complexes with tri(phenyl)antimony(V) halides have

been synthesised by the reactions in 1:1 or 1:2 stoichiometric ratios, having distorted

squarpyramidal/trigonalbipyramidal or octahedral geometries. The pentavalent

antimonials exhibit significant activities as antimicrobial agents, fungicides, catalysts

and antioxidants [17]. The triphenylantimony (V) diiodide in moist acetonitrile give

(Ph3SbI)2O molecules with Sb-O bond lengths and Sb-O-Sb angle, 1.9410-

1.9437(6) A and 144.6(4) respectively [18]. New catecholate Sb(V) complexes

6

synthesized through oxidative addition of o-quinones inti tri(phenyl)antimony(V)

precursours have also been reported[19, 20].

A series of oxo-bridged antimonials like bis(triphenyl/methylantimony)oxo4-

acylpyrazol-5-ones have been reported. The fluoromethylbenzoate ligands containing

pentavalent antimonials have been synthesized by treating with

tris(phenyl)antimony(V) dihalide in 1:1 or 1:2 stoichiometries stabilized by

intermolecular interactions have also been documented in the recent years [21, 22].

Pd(PPh3)4 catalyzed base-free Suzuki-coupling reactions between triphenylantimony

(V)carboxylates and phenylboronic acids to produce biaryl derivatives are reported in

literature[23].

Tri- and tetraphenylantimony (V) derivatives containing carboxylate ligands

have been reported with coordination environment (ArCOO)2SbPh3 or

(ArCOO)SbPh4. Triorganoantimony(V) complex has been synthesized by reacting

Ph3SbCl2 with acetylferroceneoxime in 1:2 ratio [24-26].

Bis(triorganosiloxy)triphenylantimony complexes, oxobridged species like

[SbPh3X]2O and [SbMe3X]2O with alkali metal salts of carboxylic acids to lead

[R3Sb(OOCR)]2O and R3Sb(OOCR)2 derivatives, arylantimony(V)

tris(phenyl)germanylpropionates with the formula (Ph3GeCHR1CHR2CO2)nSbAr(5-n)

(R1=H, Ph, R2=H, CH3, n-1, 2), derivatives of demethylcantharimide with anticancer

activities have been reported [27-31]. The silver salts [AgO2CC(OH)R1R2] of

αhydroxy carboxylic acid react with SbPh3Cl2 to produce cyclometalled

complexes.The salts of N-heterocylic carboxylic acidsreact with Ph3/Me3SbBr2 to

gave compounds of the type [R3Sb(O2C–Ar)2] [32-33].

The triphenylantimony complexes of the type [(C8H4F3O2)2Sb(ph)3], found to

be in trigonal-bipyramidal geometries and the crystalshave been stabilized by the 3D

network stabilized by C-H...O H-bonds. Also some oxo-bridged binuclear

tri(phenyl)antimony(V) complexes with formulae [Sb2(C6H5)6(C6H3CINO2)2O], has

7

been reported with each antimony centerbearing five coordianted environment

resulting trigonal-bipyramidal geometry[34-39].

1.2.2. Pentavalent Antimonials With Carbohydrates as Ligands

Antimony(V) complex with a polysaccharide, named mannan, is widely used for

leishmaniasis therapy/treatment. Proposed mechanism describes the formation of

water soluble antimony-carbohydrate complex in the cells in which less toxic

antimony(V) serve as pro-drug which later converted into hazardous lower oxidation

state antimony ions in the cells. Activity of the drug may be enhanced due to

sulfhydryl-antimony exchange within the cell [40-42]. Antimony is transported to

macrophages only by interacting with carbohydrates and forming stable complex.

These macrophages are the site for division of leishmania parasite [43].

1.2.3. Pentavalent Antimonials With Nucleosides as Ligands

Researchers have explained that complex formation occurs between antimony(V) and

adenine ribonucleoside [44]. First investigation about formation of biologically active

and physically stable complex of biomolecules (ribonucleoside) hasstated that these

complexes of antimony(V)-adenine ribonucleoside can be formed in two ratios i.e. 1:1

or 1:2 [44,45]. 1H-NMR data showed that antimony(V) is attached to the

ribonucleoside through –OH functionality and ring formation occurs due to bonding

with –OH group of C2 and C3 of ligand ribose. It is proved that “antimony(V)adenine

ribonucleoside complex” is formed at greater rate in those biological system which

have acidic environment [46]. At pH=7 “antimony(V)-nucleoside complexes” show

one of the remarkable property i.e. very low dissociation rate [46a]. For example

dissociation rate for “antimony(V) guanidine monophosphate” is recorded as 1:1[46a]

and it remained as such in higher vertebrates like humans and other animals which

means, antimony is not stored in vertebrate’s body organs [47]. Two hypotheses are

given to explain the mechanism of “antimony (V)-ribonucleoside complexation [46a].

According to first hypothesis, these complexes inhibit the purine carriers of leishmania

8

parasite. Other one stated that like allopurinol i.e. a purine analog, “antimony (V)-

purine complex” impregnate within the parasitic cell and then degradation of purine

bases occur at pH=7.0 of the cell. It has been reported that the elimination of

nucleotides like GTP and ATP is accompanied by formation of these compounds [48].

1.2.4. Porphyrins containing Pentavalent Antimonials

Porphyrin exhibiting conjugates have high absorbance in visible region have been

broadly used as chemical and biological active functionalities [49]. Porphyrin based

compounds have property of a variety of catalytic processes via electron/energy

transfer by irradiating visible-light. Now a day, bio-active porphyrins have gained

interest in connection of photo inactivation [50] and photodynamic therapy (PDT)

[51]. Generally, the porphyrin complexes have tendency to form face-to-face clusters

which have low solubility even in the organic solvents. For the biological applications.

of porphyrins, water solubility is an important property in handling the porphyrins in

aqueous solution. Typically, water solubilization of metalloporphyrins is achieved by

the variation of porphyrin ring by an ionic group such as ammonium [52], pyridinium

[53], sulfonate [53e, 54], phosphonium [53a, 55]or amino carboxylate [53a]. But the

synthesis of these complexes is not an easy task. Recently water-solubilization of Sb-

porphyrins has been done by varying the axial ligands [56]. Tetraphenylporphyrin

(H2tpp) is a typical and commercially available porphyrin and can easily coordinateto

the antimony. Antimony porphyrins are able to connect covalently with axial ligands

through oxygen and nitrogen atoms, resulting in the highly stabilized complexes.

Therefore, the axial ligand ofSbporphyrins can appropriately provide a variety of

water-soluble porphyrins with bioactivity and bio affinity as well as high electron

accepting ability.

1.2.5. Pentavalent Antimonials With Dioxygen as Bridging Ligands

Dioxygen, a strong oxidizing agent, has many applications in biological systems. It is

usually inert and activated only after coordinating with metal center [57]. Several

types of biomolecules can interact with O2. For example, enzymes of biological

9

systems i.e. dioxygen enzymes necessary for cell reaction, require oxygen and many

other species act as oxygen storage and carriers. In some biological systems redox

reactions are catalyzed by coordination of metalloproteins with O2. These

metalloproteins activate the O2 and help in completion of cell reactions. There is need

to replace natural O2 with its synthetic form to enhance the rate of redox reactions in

biological systems. Researchers are in the quest of finding new, easy and ideal

biological systems for production of dioxygen.

There are a large number of metal complexes to which reversible binding of

O2 takes place [58]. Though, it is a unique process and requires special conditions for

recognition of this bonding mode. The conditions required to inhibit irreversible

oxidation of O2 species are: steric hindrance in metal complexes, low temperature and

immobilization [59]. Though, researchers are trying to find out replacement of O2 as

carriers and transporters but, dioxygen is still ranked first in the biological perspective.

Mechanism of “dioxygen and transition-metal complexes” involves the transfer of

electrons from the attached transition metal to the attached ligand antibonding p-

orbitals i.e. O2. It is investigated that O2-active species can be synthesized by using

antimony in complexation reaction with O2 instead of using any other transition-metal.

1.3. Antimonials As Drugs: Merits and Demerits

The therapeutic history of antimony based compounds/drugs is dates back to medieval

ages since Paracelsus (1493-1541) used antimony powder and its compounds for the

treatment of common diseases of the time. Later on this therapy was rejected by

medical practitioners due to toxic effects. In parallel, the efforts for the development

of safer antimony based drugs with minimum residual effects of antimony (III) were

made rapidly. Treatment of leishmaniasis with pentavalent antimony complexes has

been started since 1940s. These are the first line drugs to treat all types of

leishmaniasis. Antimony (III) / (V) compounds have also been known for their

potential biological activity against some microbial and parasitic infections [60-

65].Organoantimony (III) / (V) complex have alsoshown anti-tumor activities. These

10

compounds may be exploited for development of new drugs in order to treat different

types of tumor [60, 64, 66].Recent studies have revealed that like other organo

transition metal complexes, organoantimony (III) / (V) compounds have also known

for anticancer activities [60, 61, 66].Many Organoantimony (III) / (V) compounds

showed anti-bacterial activity against different bacterial strains[6766].Several reports

indicated the antifungal activity of antimony compounds against plants and animal

pathogenic fungi[70-72]. However, very few literature references have been found in

this regard so far [71]. Organoantimony (III) / (V) compounds are also known for their

anti feedant activities [65, 73].

Despite these applications, there are several limitations in clinical use of

pentavalent antimonials in therapy of leishmaniasis [74, 75]. Very careful medical

supervision is required for this therapy as administration of these compounds is only

done by intramuscular injections on daily basis, for at least three weeks. It often results

in local pain and certain side effects which typically include abdominal colic,

vomiting, diarrhea, nausea, skin rashes, weakness, myalgia, hepatotoxicity, along with

cardiotoxicity. Another main issue to cure this disease is the appearance of resistance

against drugs [76]. The reason behind that is improper use and incomplete treatment.

It has been observed that only few (26%) patients were given treatment as stated by

prescription. These mishandling of antileishmanial drugs in Bihar state of India was

a major cause of the drug resistance. “Pentamidine” and “amphotericin B” are the

drugs used in place of that described above. These are also limited due to parenteral

administration and by severe side effects. However, besides all the above mentioned

issues, antimonial drugs are still first choice for the medical practitioners worldwide.

So, there is need to develop new series of effective compounds similar to sodium

stibogluconate (SSG) and meglumine antimoniate with well-established physical and

structural chemistry [77-80].

11

1.4. Biological applications of Antimony (V) complexes

The uses of metal complexes (inorganic compounds) in medicines have been started

many centuries ago. Many metals and their complexes have significant medicinal

applications like Pt and Pd (anti-tumor agents), As (bactericides), Sb (anti protozoal),

Au (Arthritis, gout), Bi (skin injuries, diarrhea, alimentary diseases), Ag ( anti-septic

agent, Ga (antitumor agent), Co (vitamin B12), Li (manic depression),

Cu (algicide, fungicide, insecticide), Mn (anti-fungal, Parkinson’s disease), Ru, Rh

and Os (experimental antitumor agents), Os (anti-arthritis), Hg (anti-septic), Rb (an

alternative to potassium in muscular dystrophy, protects from side effects of heart

drugs), Zn (fungicide) and Sn (anti-microbial agents) [81].

Antimony has been used for several centuries for therapeutic purposes. During

ancient Egypt, antimony was used to treat fever and skin irritations. Antimony

compounds have well known anti-parasitic effects. The mode of action and

biochemistry of antimony compounds is not clear. It is believed that the proteins and

enzymes are major targets for antimony [82].

1.5. Some Important Antimony Based Therapeutic drugs

The use of antimony in medicinal treatment has been started since sixteenth century

owing to emetic effect. Antimony compounds have also found their role in medication

of ulcers. Wine slowly develops emetic properties when it is allowed to stand in

antimony goblets, due to formation of tartar emetic by interaction of tartaric acid with

antimony [83]. After sixteenth century, the crude antimony drugs were abandoned due

to toxicity issues. However in the early twentieth century, the use of antimony in

medicine regained importance on basis of its antiparasitic impact against

trypanosomiasis.

12

Anti-leishmanial Agents

Leishmania are the parasitic protozoan from the family Trypanosomatidae.

Leishmaniasis is transmitted through sandflies vector from Phlebotomus genus

initially and later on also from Lutzomyia. Different types of Leishmaniasis are

appeared as cutaneous which involve lesions, mucocutaneous and visceral damaging

the vital organs [84-86]. The Leishmania parasite has two stages, one is promastigote

(sandfly stage) and other is amastigote (mammalian stage). It reproduces in the

intestine of the sand fly and becomes infective in 1-3 weeks. The parasite is passed on

when the sandfly bites its next vertebrate victim. Sandflies turns to be more active

from dusk to dawn. About 20 species of Leishmania causes disease in humans, while

30 sandfly species act as vectors. Leishmania parasite has two modes of transmission:

(1) which involve transfer of parasite from animals to human is termed as zoonotic (2)

anthroponotic in which vector transmitted from human to other animals. However it

is mainly a zoonotic disease [87, 88].

Fig 1.1. Life Cycle of Leishmania Parasite [Center for Disease Control (US)] Leishmania is

a tropical parasitic disease, which is widespread in 98 countries, mainly among people of

under developed countries; about 1.5 million new cases per year with 90% of cases have

13

been reported from Bangladesh, Nepal, India, Ethiopia, Brazil and Sudan. 12 million people

around the world are affected by leishmaniasis, with approximately 70,000 deaths every

year. According to the WHO reports, Leishmaniasis is the 6th largest in the epidemic

diseases in the 3rd world. [89-91].

The potassium antimony (III) tartrate [tartar emetic] was the first antimonial

compound used against leishmaniasis in 1913. This compound was very poisonous,

as it contains antimony (III), a proven toxic form of antimony. In 1940s, antimony

(III) complexes were out classed by the more effective and safe antimony (V)

compounds, sodium stibogluconate and meglumine antimoniate marketed as

Pentostam and Glucantime, repectively. They are 10 times less harmful to vertebrates

than antimony (III) salts [92].

Mode of Action

As mentioned in the previous sections, the mode of action of antimony (V) compounds

in the treatment of leishmaniasis is not well understood. It is not obvious that which

form of antimony (III) or (V) is playing role in activity of such drugs. Previous studies

portray that Sb (V) act as a prodrug; it is supposed that reduction of pentavalent

antimony occurs into more active trivalent antimony. In vivo reduction of part of Sb

(V) into (III) is the evidence of this model [72]. Different thiols are involved in this

reduction. These include: Glutathione (GSH), a principal thiol in the cell cytosol of

mammals, trypanothione [T(SH)2], an essential thiol within leishmania parasite and

the lysosomes contains primary thiols cysteinyl-glycine (Cys-Gly) and cysteine (Cys)

[93-100]. The reduction is favoured at low pH and higher temperature. Within

leishmania parasite, reduction of Sb (V) occurs by T(SH)2, while in the acidic

environment of mammalian cells Sb (V) reduces by Cys or Cys-Gly. Reduction take

place favourably in amastigotes [95], having higher temperature and lower

intracellular pH.Furthermore it is proposed that Sb(V) undergoes reduction to Sb(III)

due to contribution of enzymes, thiol-dependent reductase or antimoniate

reductase[101,102].

14

It is supposed that mechanism of action may include the interaction of Sb(III)

with zinc-finger protein or trypanothione reductase (TR). The trypanothione causes

the reduction of T(SH)2 and protection of trypanosomatids from heavy metal toxicity

and oxidative stress. Antimony (III) complexes have been reported to inhibit

trypanothione reductase, causing interference with metabolism of trypanothione and

hence pumping out trypanothione and Glutathione from cells of parasite. Another

study reported that Sb(III) has the ability to eject the Zn(II) and involved in binding to

a CCHC zinc finger peptide mode. In zinc finger domain, a number of amino acid

residues, usually histidines and cysteines are coordinated to the zinc atom. This

framework is associated with interaction of protein-protein and protein with nucleic

acid as well as other variety of functions, such as recognition of DNA, packaging of

RNA, transcriptional activation, folding of protein, lipid binding, cell differentiation,

growth and regulation of apoptosis [103, 104]

On the other hand, direct involvement of Sb (V) in mechanism of action is

suggested due to the capability of the antimony drugs to interfere with the nucleoside

metabolism [105] and to inhibit a leishmania topoisomerase [106, 107]. It has been

reported that sodium stibogluconate inhibited type-I DNA topoisomerase from

Leishmania donovani [110, 111].These studies and the fact that nucleosides and

polynucleotides contains a large number of nitrogen and oxygen donor sites for metal

ions suggest that nucleosides might be a target for pentavalent antimonials.

As antimony has high affinity for sulphur and nitrogen containing ligands so,

mechanism of leishmanial inhibition is most likely due to coordination with molecules

containing -SH group, which includes proteins, peptides, enzymes and thiols.

Antimony (V) has also been reported to form complex with adenine ribonucleoside.

The effectiveness and 10 times less toxicity of the pentavalent antimony complexes

have make them the first choice for the therapy of leishmaniasis [108-112]. So far two

models have been suggested for the probable mode of action of antimonial drugs

against leishmaniasis are as follows [110].

15

Antiviral Agents

Hepatitis-C virus is among the most lethal viruses and is found in blood. Sodium

stibogluconate has been reported to suppress replication of HCV in a section of human

liver which was freshly taken from patient infected with HCV [111]. Later on this

impact of the drug was confirmed against cell line and was found to be suitable for

HCV infection.

Sodium Stibogluconate [Pentostam]

16

Anti-HIV Agents

In the treatment of AIDS, antimoniotungstate (HPA-23) with formula of

[(NH4)17Na(NaSb9W21O86).14H2O] has beenfound to be very effective.This

compound reduces HIV levels and inhibit several DNA and RNA viruses. After this

investigation, the survey for other polyoxometalates as an active anti-HIV agents has

been started [112].

Anticancer Agents

Antimony compounds also showed anti-cancer activities. In vitro cytotoxicity of

potassium antimony tartrate against lung cancer has been evaluated, having IC50 value

of 4.2-322 μg/ml. This complex was proved to be active as clinically available drugs

for the treatment of cancer e.g. doxorubicin and cisplatin [113]. Antimony has also

showed remarkable therapeutic behavior in patients suffering from acute

promyelocytic leukemia [114]. Sodium stibogluconate exhibited substantial

anticancer activity as well [115, 116] and appeared to inhibit tumors better than

suramin, a compound having its well-known anti-neoplastic activity [115].

Potassium Antimony Tartrate

1.6. STRUCTURE ACTIVITY RELATIONSHIP

The activity of organoantimony complexes is essentially dependent upon the nature

and number of alkyl/aryl moieties (R) attached with metal center. Anionic groups

17

(X) attached to the metal center have small influence on biological potential of

organoantimony compounds and are not as much important as that of cationic groups

[116].

Bioactivity potential of organoantimony derivatives is dependent on geometry

of the complex and number and nature of the alkyl/aryl groups. Trivalent complexes

are more active than their organotincongerers. However, there is not any

otheranticancer drug which is as widely used as cisplatin. Antimony(III) adopts a

geometry of distorted pseudo-trigonalbipyramidal and also hasa lone pair atequatorial

position. The preliminary results have shown that the coordination of antimony(III)

by the ligands such as polydentate carboxylic acid results in the compounds with

greater biological activity than displayed by the non-coordinated ligands [117].

The pentavalent complexes are normally trigonal bipyramidal but sometimes

adopt simple octahedral geometry. They are 10 times less poisonous and more

effective than antimony(III) equivalents. These pentavalent antimonials became first-

line therapeutic drugs for leishmaniasis therapies [118]. If carbohydrates are attached

ligands to antimony center then solubility of the drug is enhanced which leads to the

transfer of antimony to macrophages and finally metabolic conversion of less toxic

antimony (V) to highly active antimony (III) and this reduction takes place in the

parasitic cell. Structural comparison of the active and inactive compounds suggested

that the availability of coordination position at the metal center and the stability of

alkyl/aryl-metal bondsenhance the bioactivity.

1.7. AIMS AND OBJECTIVES

Antimony (V) complexes have gained a distinctive position among the current

antileishmanial drugs. It is necessary to find out new drugs having better

leishmanicidal properties than previously known organoantimony drugs which have

become resistant to the disease and parasite. In order to achieve these objectives, more

focus should be on the interdisciplinary research work involving synthesis of new

compounds along with diagnosis of biological properties, for better perception of this

research work. This project has been designed for thesynthesis, biological assessment

18

and characterization of organoantimony (V) complexes over here in Pakistan by using

existing research facilities.This research work is primarily based on applied chemistry

and biology. Financial and scholastic obligations were trailed firmly.

1.8. PLAN OF WORK

Synthesis of different types of commercially available oxygen donor ligands

(derivatives of cinnamic acid) and organoantimony (V) complexes will be done.

Synthesized cinnamic acid derivatives i.e. oxygen donor ligands will be reacted with

pentavalent organoantimony halides to assemble tris(organo)antimony (V)

carboxylates. Different stoichiometric amounts and solvents like THF, diethyl-ether

and toluene were tested to ensure the maximum Final yield. Principally, synthesized

organoantimony (V) complexes would be tested for leishmanicidal properties. Then,

other biological activities of these compounds will also be performed such as

anticancer, alpha amylase and antibacterial activities.

1.8.1. Choice of Ligands

Cinnamic acid and its derivatives (oxygen donor ligands) are naturally occurring

materials. These cinnamic acid derivatives have a common functionality i.e. “3phenyl

acrylic acid”. There are three attachment sites present i.e. phenyl ring, carboxylic

group, andα, β-unsaturated carbon atoms. Addition reactions occur at carboxylic

group whilephenyl ring and α, β-unsaturated carbon atoms are involved in substitution

reactions. These properties of cinnamic acid and its derivatives gained much

consideration in medicinal field for the synthesis of anti-cancer drugs. Before 1905,

these medicinal applications and anti-cancer potential of cinnamic acid and their

derivatives was not reported. More attention has been given to these compounds in

the last twenty years to find out their anti-cancer ability and other potential biological

properties. We have synthesized different antimony(V) complexes [R3Sb(OOCR')2],

with R=phenyl and p-tolyl and R'=derivatives of cinnamic acids and also investigated

their various biological applications.

19

1.8.2. Choice of Metal and Targets for Biological Studies

First introduction of antimony in medical science was reported in ancient Egyptians

age. It gained huge importance because of its emetic properties. During the ancient

Egyptians age, skin diseases and different types of fevers were treated by using

antimony [119]. In past, various types of ulcers were treated with antimony containing

compounds. But, in the modern world researchers are interested in antiparasitic

properties of antimony against trypanosome infection i.e. leishmaniasis which were

reported in 1930’s after the discovery of urea stibamine (an antimony containing

compound). Antimony based drugs have a modest role in the prevailing anti-

leishmanial therapies. On the basis of biological potential of antimony it is emphasized

to synthesize new antimony based compounds and investigate their leishmanicidal as

well as other biological properties.

20

References

1. Barrett, D. Biochem-Biophys-Acta, 2002, 1587, 224.

2. Gorbach, S. L. Gastroenterology. 1990, 99(3), 863-875.

3. Wang, C. Y. “Antimony” 2nd Edition, Charles Graffin and Company Limited,

London.

4. Abd-El-Aziz, A. S., Charles, E. C. Jr., Charles, U. P. Jr., Sheats, J. E., Zeldin, M.

Macromolecules Containing Metal and Metal-Like Elements, Volume 3: Biomedical

Applications, ISBN: 0-471-66737-4. Copyright 2004, John Wiley & Sons, Inc.

5. Yamamoto, A. “Organotransition Metal Chemistry, Fundamental Concepts and

Application”. ISBN: 978-0-471-89171-0, 1991.

6. Furniss, B. S., Hannaford, A. J., Smith, P. W. G., Tatchell, A. R. “Vogel’s Text

Book of Practical Organic Chemistry” 3rd Edition.

7. Tiekink, E.R.T. Crit. Rev. Oncol. Hematol. 2002, 42, 217.

8. Wang, G.-C., Lu, Y.-N., Xiao, J., Yu, L., Song, H.-B., Li, j.- S., Cui, J.- R., Wang,

R.-Q., Ran, F.-X. J. Organomet. Chem. 2005, 690, 151.

9. Tracy, J. W., Webster, L.T., Drugs used in the chemotherapy of protozoal

infections. In: Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W.,

Gilman, A. G., editors. The Pharmacological basis of therapeuties, 9th ed. New

York: McGraw-Hill, 1995, 987.

10. Berman, D. J. Rev. Infect. Dis. 1988, 10, 560.

11. Testerdalderup, C. B. M. “Antiprotozoal drugs. Inc, Dukes MNG, editor.

Meyler's Side effects of drugs”, 13th ed. Amsterdam: Elsevier, 1996,799.

12. Lee, M. B., Gilbert, H. M. Infect. Med. 1999, 16, 37.

13. Sundar, S., Agrawal, N., Arora, R. Clin. Infect. Dis.2009, 49 (6), 850.

14. Badaro, R., Lobo, I., Munos, A. J. Infect. Dis.2006, 194 (8), 1151.

21

15. Matsumoto, J., Tanimura, S.-i., Shiragami, T., Yasuda, M., Physical Chemistry

Chemical Physics. 2009, 11 (42), 9766-9771.

16. Holmes, R. R., Accounts of Chemical Research. 1989, 22 (5), 190-197.

17. Matsumoto, J., Shiragami, T., Yasuda, M., Chemistry Letters.2008, 37 (8),

886887.

18. Yasuda, M., Nakahara, T., Matsumoto, T., Shiragami, T., Matsumoto, J., Yokoi,

H., Hirano, T., Hirakawa, K., Journal of Photochemistry and Photobiology A:

Chemistry. 2009, 205 (2), 210-214.

19. Matsumoto, J., Tanimura, S.-i., Shiragami, T., Yasuda, M., Journal of Porphyrins

and Phthalocyanines. 2012, 16 (02), 210-217.

20. Matsumoto, J., Shinbara, T., Tanimura, S.-i., Matsumoto, T., Shiragami, T.,

Yokoi, H., Nosaka, Y., Okazaki, S., Hirakawa, K., Yasuda, M., Journal of

Photochemistry and Photobiology A: Chemistry. 2011, 218 (1), 178-184.

21. Matsumoto, J., Kubo, T., Shinbara, T., Matsuda, N., Shiragami, T., Fujitsuka,

M., Majima, T., Yasuda, M., Bulletin of the Chemical Society of Japan. 2013, 86

(11), 1240-1247.

22. Matsumoto, J., Beppu, T., Shiragami, T., Yasuda, M., Journal of Photochemistry

and Photobiology A: Chemistry. 2012, 249, 47-52.

23. Tiekink, E. R., Appl. Organometal. Chem.1991, 5 (1), 1-23.

24. Wen, L., Yin, H., Wang D., Cui, L., Yang, M., Acta. Cryst., 2008, E64, m1426.

25. Li, J. S., Ma, Y. Q., Cui, J. R., Wang, R. Q., Applied Organometallic

Chemistry.2001, 15 (7), 639-645.

26. Wainwright, M., Anti-Cancer Agents in Medicinal Chemistry (Formerly Current

Medicinal Chemistry-Anti-Cancer Agents) 2008, 8 (3), 280-291.

27. Quan, L., Yin, H., Wang, D., Acta. Cryst., 2008, E64, m1503.

28. Chaudhari, K. R., Jain, V. K., Sagoria, V. S., Tiekink, E.R.T., J. Organomet.

Chem., 2007. 692(22), 4928-4932.

29. Gibbons, M.N., Sowerby, D.B., J. Organomet. Chem., 1998, 555(2), 271-278.

30. Wang, G.-C., Xiao, J., Yu, L., Li, J.-S., Cui, J.-R., Wang, R.-Q., Ran, F.-X.,

Journal of Organometallic Chemistry.2004, 689 (9), 1631-1638.

22

31. Wang, G. -C.,Xiao, J., Yu, L., Li, J. -S., Cui, J. -R., Wang, R. -Q., Ran, F. -X., J.

Organomet. Chem., 2004, 689(9), 1631-1638.

32. Quan, L., Yin, H., Cui, L.,Yang, M., Wang, D., Acta. Cryst., 2009, E65,

m656m657.

33. Barucki, H., Coles, S. J., Costello, J. F., Hursthouse, M. B., J. Organomet.

Chem., 2001, 622(1-2), 265-273.

34. Yu, L., Ma, Y. -Q., Wang, G. -C., Li, J. -S., Heteroatom Chemistry, 2004, 15(1),

32-36.

35. Quan, L., Yin, H., Wang, D., Acta. Cryst., 2009, E65, m99.

36. Poddel, A. I., Smolyaninov, I. V., Kurskii, Y. A., Fukin. G.K., Berberova, N.T.,

Cherkasov, V.K., Abakumov, G.A., J. Organomet. Chem., 2010, 695(8),

12151224.

37. Jin, R.-H., Aoki, S., Shima, K., Chemical Communications.1996, (16), 19391940.

38. Nunn, M., Begley, M.J., Sowerby, D.B., Polyhedron, 1996, 15(19), 3167-3174.

39. Rozenbaum, W., Dormont, D., Spire, B., Vilmer, E., Gentilini, M., Griscelli, C.,

Montagnier, L., Barre-Sinoussi, F., Chermann, J., The Lancet. 1985, 325, 450451.

40. Cantos, G., Barbieri, C., Iacomini, M., Gorin, P., Travassos, L., Biochemical

Journal. 1993, 289 (1), 155-160.

41. Carraher Jr, C. E., Naas, M. D., Giron, D. J., Cerutis, D. R., Journal of

Macromolecular Science-Chemistry.1983, 19 (8-9), 1101-1120

42. Roberts, W. L., Rainey, P. M., Analytical Biochemistry.1993, 211 (1), 1-6.

43. Demicheli, C., Santos, L. S., Ferreira, C. S., Bouchemal, N., Hantz, E., Eberlin,

M. N., Frézard, F., Inorganica Chimica Acta. 2006, 359 (1), 159-167.

44. Chai, Y., Yan, S., Wong, I. L., Chow, L. M., Sun, H., Journal of inorganic

Biochemistry. 2005, 99 (12), 2257-2263.

45. Hansen, H. R., Pergantis, S. A., Analytical and Bioanalytical Chemistry.2006,

385 (5), 821-833.

46. Roberts, W. L., Berman, J. D., Rainey, P. M., Antimicrobial Agents and

Chemotherapy.1995, 39 (6), 1234-1239.

23

47. (a) Berman, J. D., Waddell, D., Hanson, B., Antimicrobial Agents and

Chemotherapy.1985, 27 (6), 916-920, (b) Herman, J. D., Gallalee, J. V., Best, J.

M., Biochemical Pharmacology.1987, 36 (2), 197-201.

48. Dos-Santos Ferreira, C., De-Castro Pimenta, A. M., Demicheli, C., Frezard, F., -

Biometals, 2006, 19 (5), 573-581

49. Shiragami, T., Matsumoto, J., Inoue, H., Yasuda, M., Journal of Photochemistry

and Photobiology C: Photochemistry Reviews.2005, 6 (4), 227-248.

50. (a) Josefsen, L. B., Boyle, R. W., Theranostics. 2012, 2 (9), 916, (b) Kudinova,

N., Berezov, T., Biochemistry (Moscow) Supplement Series B: Biomedical

Chemistry.2010, 4 (1), 95-103,

51. Nyman, E. S., Hynninen, P. H., Journal of Photochemistry and Photobiology B:

Biology.2004, 73 (1), 1-28.

52. (a) Lang, K., Mosinger, J., Wagnerová, D., Coordination Chemistry

Reviews.2004, 248 (3), 321-350, (b) Banfi, S., Caruso, E., Buccafurni, L., Battini,

V., Zazzaron, S., Barbieri, P., Orlandi, V., Journal of photochemistry and

photobiology B: Biology.2006, 85 (1), 28-38, (c) Batinic-Haberle, I., Spasojevic,

I., Hubert, M. T., Tovmasyan, A., Rajic, Z., Clair, D. K. S.,

Vujaskovic, Z., Dewhirst, M. W., Piganelli, J. D., Amino Acids.2012, 42 (1),

95113, (d) Kano, K., Fukuda, K., Wakami, H., Nishiyabu, R., Pasternack, R. F.,

Journal of the American Chemical Society.2000, 122 (31), 7494-7502, (e) Kubát,

P., Lang, K., Anzenbacher Jr, P., Jursíková, K., Král, V., Ehrenberg, B., Journal

of the Chemical Society, Perkin Transactions-I.2000, (6), 933-941.

53. Dąbrowski, J. M., Pereira, M. M., Arnaut, L. G., Monteiro, C. J., Peixoto, A. F.,

Karocki, A., Urbańska, K., Stochel, G., Photochemistry and photobiology.2007,

83 (4), 897-903.

54. Jin, R.-H., Aoki, S., Shima, K., Journal of the Chemical Society, Faraday

Transactions.1997, 93 (22), 3945-3953.

55. Sharutin, V., Sharutina, O., Pakusina, A., Platonova, T., Fukin, G., Zakharov, L.,

Russian Journal of Coordination Chemistry.2001, 27 (5), 368-370.

24

56. Kasuga, N. C., Onodera, K., Nakano, S., Hayashi, K., Nomiya, K., Journal of

Inorganic Biochemistry.2006, 100 (7), 1176-1186.

57. Solomon, E. I., Brunold, T. C., Davis, M. I., Kemsley, J. N., Lee, S.-K., Lehnert,

N., Neese, F., Skulan, A. J., Yang, Y.-S., Zhou, J., Chemical Reviews. 2000, 100

(1), 235-350.

58. Harrison, P. M., Hoare, R. J., Metals in Biochemistry. Springer: 1980.

59. Blunden, S. J., Hill, R., Inorganica Chimica Acta.1985, 98 (1), L7-L8.

60. Silvestru, C., Haiduc, I., Tiekink, E.R., D. de Vos, M.i. Biesemans, R. Willem,

M. Gielen, Appl. Organometal. Chem., 1995, 9,597-607.

61. G.-C. Wang, J. Xiao, L. Yu, J.-S. Li, J.-R. Cui, R.-Q. Wang, F.-X. Ran, J.

Organomet. Chem., 2004, 689, 1631-1638.

62. Carraher Jr, C.E., M. D. Naas, D. J. Giron, D. R. Cerutis, Journal of

Macromolecular Science-Chemistry 1983, 19, 1101-1120.

63. Kant, R., Singhal, K., S.K. Shukla, K. Chandrashekar, A. Saxena, A. Ranjan, P.

Raj, Phosphorus, Sulfur, and Silicon, 2008, 183, 2029-2039.

64. Wang, G.-C., Lu, Y.-N., Xiao, J., L. Yu, H.-B. Song, J.-S. Li, J.-R. Cui, R.-Q.

Wang, F.-X. Ran, J. Organomet. Chem., 2005, 690,151-156.

65. Nomiya, K., Tsuda, K., Sudoh, T., Oda, M., Journal of inorganic biochemistry,

68 1997, 39-44.

66. Nomiya, K., Noguchi, R., Ohsawa, K., K. Tsuda, M. Oda, Journal of inorganic

biochemistry, 2000, 78, 363-370.

67. Nomiya, K., Noguchi, R., T. Shigeta, Y. Kondoh, K. Tsuda, K. Ohsawa, N.

Chikaraishi-Kasuga, M. Oda, Bulletin of the Chemical Society of Japan 2000, 73,

1143-1152.

68. Srivastava, M. K., Mishra, B., Nizamuddin, M., Indian Journal Of Chemistry Section

B 2001, 40, 342-344.

69. Tweedy, B., Phytopathology 1964, 55, 910-914.

70. Tarafder, M.T.H., Ali, M.A., Wee, D.J., K. Azahari, S. Silong, K.A. Crouse,

Transition Metal Chemistry. 2000, 25, 456-460.

25

71. Dethier, V., Browne, B.L., C.N. Smith, Journal of Economic Entomology 1960,

53,134-136.

72. Marsden, P.D. “Revista da Sociedade Brasileira de Medicina Tropical”, 1985,

18, 187-198.

73. Berman, J., Clinical infectious diseases 1997, 24, 684-703.

74. Guerin, P.J., Olliaro, P. S. Sundar, M. Boelaert, S.L. Croft, P. Desjeux, M.K.

Wasunna, A.D. Bryceson, The Lancet infectious diseases 2 (2002) 494-501.

75. Sundar, S., More, D.K., Singh, M.K., Singh, V.P., Sharma, S., Makharia, A.,

Kumar, P.C., Murray, H.W. Clinical Infectious Diseases 31 (2000) 1104-1107.

76. Sundar, S., Thakur, B., Tandon, A., Agrawal, N., Mishra, C., Mahaptra, T., Singh,

V.P. British Medical Journal 308 (1994) 307.

77. Yasinzai, M., Khan, M., Nadhman, A., Shahnaz, G. Future Medicinal Chemistry

5 (2013) 1877-1888.

78. Baiocco, P., Colotti, G., Franceschini, S., Ilari, A. Journal of Medicinal Chemistry

52 (2009) 2603-2612.

79. Abd-El-Aziz, A. S., Carraher, C. E., Pittman, C.U., Sheats, J.E., Zeldin, M.,

“Macromolecules Containing Metal and Metal-Like Elements, A Half-Century of

Metal-and Metalloid-Containing Polymers”, John Wiley & Sons, 2004.

80. Tabbì, G., Cassino, C., Cavigiolio, G., Colangelo, D., Ghiglia, A., Viano, I.,

Osella, D. Journal of medicinal chemistry 45 (2002) 5786-5796.

81. Harry, A.G., Butler, W.E., Manton, J.C., Pryce, M.T., Donovan, N. O., Crown,

J., Rai, D.K., Kenny, P.T., J. Organomet. Chem.,766 (2014) 1-12.

82. Vannier-Santos, M., Martiny, A., Souza, W.D. Current Pharmaceutical Design 8

(2002) 297-318.

83. Weniger, B., Robledo, S., Arango, G.J., Deharo, E., Aragón, R., Muñoz, V.,

Callapa, J., Lobstein, A., Anton, R. Journal of ethnopharmacology 78 (2001) 193-

200.

84. Rauf, M. K., Shaheen, U., Asghar, F., Badshah, A., Aadhman, N, Azam, S., Ali,

M. I., Shahnaz, G., Yasinzai, M., Archiv der Pharmazie. 2016, 349, 50-62.

26

85. Seaman, J., Mercer, A.J., Sondorp, H.E., Herwaldt, B.L. Annals of Internal

Medicine 124 (1996) 664-672.

86. Ashford, R. International Journal for Parasitology 2000, 30, 1269-1281.

87. J. Alvar, I.D. Velez, C. Bern, M. Herrero, P. Desjeux, J. Cano, J. Jannin, M. den

Boer, W.L.C. Team, PloS One 7 (2012) e35671.

88. J. Mishra, A. Saxena, S. Singh, Current medicinal chemistry 14 (2007) 11531169.

89. P. Chirac, E. Torreele, The Lancet 367 (2006) 1560-1561.

90. Venugopal, B., T.D. Luckey, “Metal toxicity in mammals. Volume 2. Chemical

toxicity of metals and metalloids”, Plenum Press., 1978.

91. Duffin, J., P. René, Journal of the history of medicine and allied sciences 46

(1991) 440-456.

92. Burguera, J., Burguera, M., Y. DE PENA, A. Lugo, N. Anez, Trace elements in

medicine 10 (1993) 66-70.

93. Shaked-Mishan, P., N. Ulrich, M. Ephros, D. Zilberstein, Journal of Biological

Chemistry 276 (2001) 3971-3976.

94. dos Santos Ferreira, C., Martins, P.S., Demicheli, C., Brochu, C., Ouellette, M.,

Frézard F., Biometals 16 (2003) 441-446.

95. F. Frézard, C. Demicheli, C.S. Ferreira, M.A. Costa, Antimicrobial agents and

chemotherapy, 45 (2001) 913-916.

96. S. Yan, F. Li, K. Ding, H. Sun, Journal of Biological Inorganic Chemistry, 2003,

8 ,689-697.

97. Fairlamb, A.H., Cerami, A., Annual Reviews In Microbiology 1992, 46, 695-729.

98. D. Gainey, S. Short, K.L. McCoy, Journal of cellular physiology 1996, 168, 248-

254.

99. Denton, H., McGregor, J. C., Coombs, G. H., Biochemical Journal 2004, 381,

405-412.

100. Zhou, Y., Messier, N., Ouellette, M., Rosen, B.P., R. Mukhopadhyay, Journal of

Biological Chemistry, 2004, 279, 37445-37451.

27

101. Demicheli, C., Frézard, F., Mangrum, J. B., Farrell, N.P., Chemical

Communications , 2008,4828-4830.

102. Leon, O., M. Roth, Biological Research 2000, 33, 21-30.

103. Chakraborty, A. K., Majumder, H. K., Biochemical and biophysical research

communications, 1988, 152, 605-611.

104. Lucumi A., Robledo, S., Gama V., Saravia, N. G., Antimicrobial agents and

chemotherapy 1998, 42, 1990-1995.

105. Berman, J. D., Review of Infectious Diseases, 1988, 10, 560-586.

106. Pezzano, H., Podo, F., Chemical Reviews 1980, 80, 365-401.

107. Johnson, J.C., Metallocene technology, Noyes Publications, 1973.

108. Frézard, F. , Demicheli, C., R.R. Ribeiro, Molecules 14 (2009) 2317-2336. 109.

Singh, P., Rausch, M.D., Lenz, R.W., Polymer Bulletin 22 (1989) 247-252.

110. Barlow, S., D. O'Hare, Chemical reviews 97 (1997) 637-670.

111. Wang, S., Peng, T.-Z., C.F. Yang, Journal of Electroanalytical Chemistry 544

(2003) 87-92.

112. Desoize, B., Anticancer Research 24 (2004) 1529-1544.

113. Yi, T., Pathak, M. K., Lindner, D. J., Ketterer, M. E., Farver, C., Borden, E.C.,

The Journal of immunology, 2002, 169, 5978-5985.

114. Yeh, C.-T., Hwang, D.-R., Lai, H.-Y., Hsu, J. T., Biochemical and biophysical

research communications 2003, 310, 537-541.

115. Goodwin, L., Transactions of the Royal Society of Tropical Medicine and Hygiene

1995, 89, 339-341.

116. Hu, et. Al., Main Group Metal Chemistry. 1997, 20 (3), 169-180.

117. Venugopal, B., Luckey, T. D., Metal Toxicity in Mammals. Volume 2. “Chemical

toxicity of metals and metalloids”. Plenum Press.1978.

118. Solomon, E. I., Brunold, T. C., Davis, M. I., Kemsley, J. N., Lee, S.-K., Lehnert,

N., Neese, F., Skulan, A. J., Yang, Y.-S., Zhou, J., Chemical Reviews.2000, 100

(1), 235-350.

119. Harrison, P. M., Hoare, R. J., Metals in Biochemistry. Springer: 1980.

28

Chapter-2

EXPERIMENTAL & CHARACTERIZATION

2.1. Chemicals and Reagents

The carboxylic acids as mentioned with the relevant synthesized complexes for the

stoichiometric calculations and Bromobenzene, 4-Bromotoluene,

2,5dimethylbromobenzene, 2-chlorobenzene, 4-chlorobenzene, 2-fluorobenzene,

4fluororobenzene, 2-trifluororomethylbenzene and magnesium turnings were

purchased from well reputed vendors and used as obtained. All solvents and reagents

were purchased from daejung S. Korea. The deutrated solvents used for multinuclear

NMR studies were purchased from Sigma-Aldrich. The solvents were distilled and

dried where deemed necessary, and stored under saturated environment of nitrogen

[1, 2].

2.2. Software and Instrumentation

The rough melting points of the synthesized compounds were determined in capillary

tubes as sample holders on MPD Mitamura apparatus, Riken Kogyo, Japan. Reported

values were used as a tool to differentiate between the starting materials and final

products.

Bruker Avance 300 MHz spectrometer was used for NMR (1H & 13C) studies

using distilled deuterated solvents. Tetramethylsilane (TMS) were used as reference

standard for chemical shift scaling at 300 and 75.5 MHz for 1H and 13C NMR

measurements, respectively. The abbreviations used for representation of the splitting

of proton resonances in 1H NMR spectra are defined as s = singlet, d = doublet and m

= multiplet pattern.

Perkin-Elmer-2000 Infrared spectrometer was used for recording of all the

FTIR spectra at 250-4000cm-1. The CHNS analysis was conducted by using LECO183

elemental analyzer.

29

Single crystal XRD analysis were carried out by using diffractometers like Rigaku

AFC7R with Mercury CCD, Bruker SMART-CCD area-detector with graphite

monochromatic (MoKα) radiation source (λ = 0.71073Å). The structures were solved

by direct methods like Sir 97 [3], and refined with Shelxl 97 [4].

2.3. General Methodology for Synthesis

2.3.1. Preparation of Organo-antimony (III) (a-f) & (V) (A-G) Precursors

To a three necks reaction flask, 0.12mol of magnesium chips/ turnings was stirred in

100 ml ether with few crystals of iodine as an activator under inert conditions. The

temperature of reaction flask was maintained at 0 to -5 °C by using a cooling mixture

and afterwards 0.12 mol of the respective aryl halide was added slowly. After attaining

the exothermic conditions and cooling, a solution of 0.02 mol of SbCl3 in ether was

added drop wise with continuos stirring for one hours. After two hours stirring, the

ether was removed under reduced pressure and triarylantimony was isolated by

solvent extraction technique by using CH2Cl2/CHCl3 and then washed the organic

layer with 1M HCl and separated the organic layer and separated the product by

removing the solvent. Dissolved the impure triarylantimony(III) in ether and treated

with liquid bromine (Scheme 1). Removed the solvent to get product and dissolved

the dibromotriaryl antimony(V) in a minimum volume of dichloromethane and kept

under slow evaporation for for the isolation of product[5-9].

Ether

Mg + RX RMgX

3RMgX + M(III)X'3 M(III)R3 + 3MgXX'

(a-g) Ether

M(III)R3 + Br2 R3M(III)Br2

(a-g) (A-G)

Where

R= -C6H5 (a, A), p-CH3C6H4 (b, B), 2,5-(CH3)2C6H3(c, C), p-ClC6H4 (d, D), o-

CF3C6H4(e, E), p-FC6H4 (f, F), o-ClC6H4 (g, G) M= Sb X= Halogens

Scheme 1. Synthesis of Organo-antimony (III) (a-g) & Organo-antimony (V) (A-G)

Precursors.

E t h e r

30

2.3.2. Synthesis of Triphenylantimony(V) Dicarboxylates (1A-18A)

The sodium/potassium salt of the carboxylic acid (0.01mol) and organo-antimony (V)

(0.005mol) were added in 75 ml of toluene, and stirred for 10 h. The sodium/potassium

salt and solvent was removed by filtering it under low pressure. The residue obtained

was dissolved in dichloromethane and kept under slow evaporation in semi sealed

bottles for crystallization. Toluene was distilled over sodiumbenzophenone ketyl and

used fresh when required.

Scheme 2. Synthesis of tri(phenyl)antimony(V) dicarboxylates (1A-18A)

31

2.3.2.1. Synthesis and Characterization (1A-18A)

Bis(2-aminobenzoato)(triphenyl)antimony(V) (1A)

The stoichiometric quantities was 1.59g (0.01 mol) potassium salt of o-aminobenzoic

acid and 2.51g (0.005 mol) tris(phenyl)antimony(V) dibromide precursor. Colourless

solid, Final yield 83%, m.p.211-212 ˚C, FTIR(cm-1) 3094 (C-Haromatic ), 3455, 3345

(C-NH2), 1663 (C=O), 1253 (C-O), 562 (Sb-C), 463 (Sb-O), 1HNMR (CDCl3) δ 5.61

(sbroad, 4H,-NH2), 6.58 (d, 2Hf, J=8.1 Hz), 6.64 (t,dds appeared as t, 2Hd, 3J=7.2 Hz),

7.22 (td,dds appeared as td, 2He, 3J=8.4Hz, 4J=1.5Hz), 7.49-7.55 (m, 9Hb, b´, j), 7.94

(dd, 4Hc, 3J= 7.8Hz, 4J=1.5Hz), 8.13 (dd, 6Ha,a´, 3J=7.2Hz, 4J=2.1Hz), 13C MR

(CDCl3) δ 113.2 (2C, C-C=O), 115.9 (2Cf), 116.4 (2Cd), 129.4 (6Cb, b´), 130.9

(3Cj),132.3 (2Cc), 133.4 (2Ce), 133.7 (6Ca, a´), 139.2(3C, ipso-C), 150.4(2C, C-NH2),

172.5 (2C, carbonyl), Anal. calcd. C32H27N2O4Sb: C, 61.46, H, 4.35, N, 4.48 Found:

C, 61.40, H, 4.33, N, 4.51.

Bis(4-methylbenzoato)(triphenyl)antimony(V) (2A)

Stoichiometric amounts were calculated as for 1A. Colourless solid, Final yield 86%,

m.p.233-235˚C, FTIR(cm-1) 3054 (C-Haromatic), 2920 (C-Haliphatic), 1611 (C=O), 1265

(C-O), 550 (Sb-C), 457 (Sb-O), 1HNMR (CDCl3) δ 2.39 (s, 6H, -CH3), 7.18 (d,

4Hd,d´,3J=7.8Hz), 7.49-7.54 (m, 9Hb, b´, j), 7.88 (d, 4Hc, c´,3J= 8.1Hz), 8.16 (dd, 6Ha,

a´,3J=7.5Hz, 4J=2.1Hz), 13CNMR (CDCl3) δ 21.6 (2C, -CH3), 128.8 (4Cd, d´), 129.4

(6Cb, b´), 129.9(2C, C-C=O), 130.0(4Cc, c´), 131.1(3Cj), 133.9(6Ca, a´), 138.6(3C,

ipsoC), 142.7(2C, CH3-), 170.4 (2C, carbonyl), Anal. calcd. for C34H29O4Sb: C,

65.51, H, 4.69 Found: C, 65.46, H, 4.65.

Bis[2-(phenylamino)benzoato](triphenyl)antimony(V)(3A)


m.p.155-156 ˚C, FTIR(cm-1) 3265 (-NH),3026 (C-Haromatic), 1629 (C=O), 1260 (CO),

564 (Sb-C), 448 (Sb-O), 1HNMR (CDCl3) δ 6.74 (td, 2He,3J=7.2Hz, 4J=1.8Hz), 7.07

(t, dds appeared as t,2Hh,3J=7.2Hz), 7.16-7.18 (m, 4Hg, f), 7.23-7.35 (m, 8Hc, c´, d, d´),

7.51-7.54 (m, 9Hb, b´, j), 8.04 (d, 2Hi, 3J=8.1Hz), 8.16 (dd, 6Ha, a´,3J= 7.2Hz, 4J=2.4Hz)

9.54 (s, 2H, -NH-), 13CNMR (CDCl3) δ 113.7 (2C, carbonyl), 114.7 (4Cc, c´), 116.8

32

(2Cg), 122.2 (6Cb, b´), 122.9 (2Ce), 129.2 (4Cd, d´), 129.6 (6Ca, a´), 131.3 (2Ci), 132.7

(2Cf), 133.4 2(Ch), 133.8 (3Cj),138.5 (2C, ipso-C), 141.2 (2C, C6H4-NHC), 147.5

(3C,C-NH-C6H6), 172.3 (2C, carbonyl), Anal. calcd. for C44H35N2O4Sb: C,

67.97, H, 4.54, N, 3.60 Found: C, 67.95, H, 4.49, N, 3.64. Bis(3,

5-dichlorobenzoato)(triphenyl)antimony(V)(4A)


m.p.145-146 ˚C, FTIR (Powder, cm-1) 3068 (C-Haromatic), 1647 (C=O), 1258 (C-O),

740 (C-Cl), 579 (Sb-C), 444 (Sb-O), 1HNMR (CDCl3) δ7.44 (st, 3He,4J=2.1Hz), 7.56-

7.59 (m, 9Hb, b´, j), 7.80 (sd, 4Hc, c´,4J=2.1Hz), 8.12 (dd, 6Ha, a´,3J= 7.2Hz,

4J=2.4Hz), 13CNMR (CDCl3) δ 128.3 (4Cc, c´), 129.7 (6Cb, b´), 131.6 (3Cj), 131.8 (2C,

C-C=O), 133.7 (6Ca, a´), 134.8 (4C, C-Cl), 135.5 (2Ce), 136.9 (3C, ipso-C), 167.5 (2C,

carbonyl), Anal. calcd. for C32H21Cl4O4Sb: C, 52.43, H, 2.89, Found: C, 52.40, H,

2.85.

Bis(propanoato)(triphenyl)antimony(V)(5A)


m.p.121-123 ˚C, FTIR(cm-1) 3057 (C-Haromatic), 2974-2937 (C-Haliphatic), 1647 (C=O),

1278 (C-O), 555 (Sb-C), 458 (Sb-O), 1HNMR (CDCl3) δ 0.93 (t, 6Hb, CH3b-CH2

a-,

3J=7.5Hz), 2.13 (q, 4Ha, CH3b-CH2

a-,3J=7.5Hz), 7.48-7.52 (m, 9Hb, b´, j), 8.03

(dd,6Ha, a´,3J=6.0Hz, 4J=2.7Hz), 13CNMR (CDCl3) δ 9.7 (2C, -CH3), 28.9 (2C, -CH2),

129.1 (6Ca, a´), 130.8 (3Cj), 133.8 (6Cb, b´), 139.0 (3C, ipso-C), 178.8 (2C, carbonyl),

Anal. calcd. for C24H25O4Sb: C, 57.74, H, 5.05, Found: C, 57.70, H, 5.01.

Bis(nicotinato)(triphenyl)antimony(V) (6A)


m.p.180-182 ˚C, FTIR(cm-1) 3054 (C-Haromatic),1654 (C=O),1587(C-N), 1269 (C-O),

562 (Sb-C),447 (Sb-O), 1HNMR (CDCl3) δ 7.28-7.32 (m, 2He), 7.50-7.56 (m, 9Hb, b´,

j), 8.12-8.18 (m,8Ha, a´, d), 8.68 (dd, 2Hf,3J=4.8Hz, 4J=1.5 Hz), 9.15 (sd, 2Hc,4J=1.5

Hz), 13CNMR (CDCl3) δ 123.1(2Ce), 128.3 (2C, C-C=O), 129.7 (6Cb, b´), 131.6 (4Cj),

33

133.8 (6Ca, a´), 136.9 (3C, ipso-C),137.4 (2Cd), 151.2 (2Cc), 152.4 (2Cf), 168.3 (2C,

carbonyl), Anal. calcd. for C30H23N2O4Sb: C, 60.33, H, 3.88, N, 4.69, Found: C,

60.29, H, 3.85, N, 4.72.

Bis(2-methoxyphenylacetato)(triphenyl)antimony(V) (7A)

Stoichiometric amounts were calculated as for 6A. Colourless solid, Final yield

85%, m.p.168-170 ˚C, FTIR(cm-1) 3018(C-Haromatic), 2926 (C-Haliphatic), 1657 (C=O),

1259 (C-O), 582 (Sb-C), 484 (Sb-O), 1HNMR (CDCl3) δ 3.39(s, 4H, -CH2-), 3.88 (s,

6H, -OCH3), 6.75 (d, 2Hf, 3J=8.1 Hz), 6.84 (t, 2Hd, 3J=7.2 Hz), 7.24 (td, dds appeared

as td, 2He,3J=7.2Hz, 4J=1.5Hz), 7.42-7.52 (m, 9Hb, b´, j), 7.91 (d, 4Hc,3J=7.8 Hz), 8.11

(dd,6Ha, a´, 3J=8.1Hz, 4J=1.2Hz), 13CNMR (CDCl3) δ 45.0 (2C, -CH2-), 55.2(2C,-

OCH3), 110.2(2C, C-CH2-), 120.6(2Cf), 123.3(2Cd), 128.2(6Cb, b´),

129.6(3Cj), 129.8(2Cc), 131.1(6Ca, a´), 135.0(2Ce), 136.1(3C, ipso-C), 157.4(2C,

COCH3), 177.3 (2C, carbonyl), Anal. calcd. for C36H33O6Sb: C, 63.27, H, 4.87,

Found: C, 63.24, H, 4.83.

Bis(4-methoxyphenylacetato)(triphenyl)antimony(V) (8A)


m.p.171-172 ˚C, FTIR(cm-1) 2936(C-Haromatic), 2840 (C-Haliphatic), 1652 (C=O), 1265

(C-O), 548 (Sb-C), 484 (Sb-O), 1HNMR (CDCl3) δ3.37 (s, 4H, -CH2-), 3.81 (s, 6H, -

OCH3), 6.75 (d(skewed), 4Hc, c´,3J=8.7Hz), 6.95 (d(skewed), 4Hd, d´, 3J=8.4Hz), 7.39

(t(skewed), 6Hb, b´, 3J=7.5Hz), 7.47 (tt(skewed), 3Hj, 3J=7.5Hz, 4J=1.2Hz ), 7.79 (dd, 6Ha, a´,

3J=8.1Hz, 4J=1.2Hz), 13CNMR (CDCl3) δ 42.3 (2C, -CH2-), 55.3 (2C, -OCH3), 113.6

(4Cd, d´), 127.7(2C, C-CH2-), 129.1(6Cb, b´), 130.2 (4Cc, c´), 130.9(3Cj), 133.8 (6Ca, a´),

137.4 (3C, ipso-C), 158.2(2C, C-OCH3), 175.2 (2C, carbonyl), Anal. calcd.

for C36H33O6Sb: C, 63.27, H, 4.87, Found: C, 63.24, H, 4.84.

Bis(p-chlorophenylacetato)(triphenyl)anitmony(V)(9A)

Stoichiometric amounts were calculated as for 8A. white crystalline solid, Final

yield 83%, m.p, 143-144 ˚C, FT-IR (cm-1) 3050(C-Haromatic), 2929 (C-Haliphatic),

1642(COOasym), 1262 (C-O), 737(C-Cl), 563(Sb-C), 453(Sb-O), 1HNMR

34

(CDCl3) δ3.39 (s, 4H, -CH2-), 6.82 (d(skewed), 4Hc, c´,3J=8.7Hz), 7.12 (d(skewed), 4Hd, d´,

3J=8.4Hz), 7.36 (t(skewed), 6Hb, b´, 3J=7.5Hz), 7.43 (tt(skewed), 3Hj,

3J=7.5Hz, 4J=1.2Hz),

7.72 (dd, 6Ha, a´, 3J=8.1Hz, 4J=1.2Hz),13C NMR (CDCl3) δ 42.5 (2C, CH2-), 113.8

(4Cd, d´), 127.8 (2C, C-CH2-), 129.7 (6Cb, b´), 131.2 (4Cc, c´), 132.5 (3Cj), 133.7 (6Ca,

a´), 138.9 (3C, ipso-C), 156.8(2C, C-Cl), 175.7 (2C, cabonyl), Anal.calcd.

C34H27Cl2O4Sb: C, 58.99, H, 3.93, Found: C, 58.92, H, 3.94.

Bis (o-formylbenzoato)(triphenyl)antimony(V) (10A)

Stoichiometric amounts were calculated as for 9A. Final yield 81%, white crystalline

solid, m.p.=147˚C. FTIR(cm-1) 3096(m) & 3079(m) (C-Haromatic), 2992(m) & 2972(m)

(C-Haliphatic), 1671(m) & 1674(s) (C=O), 1431(s), 1394(s), 1332(m), 1303(s),

1294(s)(C-O), 1267(m), 1206(m), 1127(s), 1111(m), 931(m), 859(m), 852(m), 791(s),

762(s), 687(m), 623(m), 561(m)(Sb-C), 526(m), 516(m),

456(m), 448(m)(Sb-O). 1HNMR (CDCl3) δ 7.46 (d, 2H, 3J=7.2Hz, ArH), 7.50-7.57

(m, 13H, ArH), 7.71(d, 2H, ArH, 3J=7.2Hz,), 8.14 (dd, 6H, 3J=7.2 Hz, 4J=2.4Hz,

ArH), 10.17 (s, 2H, H-C=OPh). 13CNMR (CDCl3) δ125.3 (2C), 127.6 (3C), 128.2

(6C), 129.6 (2C), 131.3 (3C), 131.6 (6C), 132.7 (2C), 134.3 (2C), 135.2 (2C), 136.8

(3C, ipso-C), 170.2 (2C, >=O), 192.7 (2C, >=O). Anal.calc. for C34H25O6Sb: C,

62.70, H, 3.87, Found: C, 62.68, H, 3.85.

Bis (4-oxo-4-p-tolylbutanoato)(triphenyl)antimony(V) (11A)

Stoichiometric amounts were calculated as for 10A. White crystalline solid, Final

yield. 76%, m.p.=128-130˚C. FTIR(cm-1) 3028(m) (C-Haromatic), 2968(m), 2844(m) &

2715(w) (C-Haliphatic), 1688(s, broad) (C=O), 1629(s), 1622(s) 1611(s), 1601(s),

1599(s), 1450(m), 1423(s), 1379(s), 1328(m), 1315(m), 1284(m), 1255(s)(C-O),

1216(s), 1175(m), 979(m), 831(m), 799(m), 693(m), 626(m), 564(m)(Sb-C),

551(m), 526(m), 516(m), 456(m), 451(m)(Sb-O). 1HNMR (CDCl3) δ 2.40 (s, 6H,

CH3), 2.58(t, 4H, 3J=5.4Hz, -CH2- ), 3.06 (t, 4H, 3J=5.4Hz, -CH2-), 7.23(d, 4H,

3J=7.2Hz, ArH), 7.43-7.51(m, 9H, ArH), 7.79 (d, 4H, 3J=7.2Hz, ArH), 7.87 (dd, 6H,

3J=7.2Hz, 4J=2.4Hz, ArH). 13CNMR (CDCl3) δ 21.6 (2C, -CH3), 34.0 (2C, -CH2-),

35

45.5 (2C, -CH2-), 129.2 (2C), 129.5 (4C), 130.9 (6C), 133.8 (6C), 134.1 (3C), 135.3

(2C), 137.7 (4C), 143.6 (3C, ipso-C), 177.3 (2C, >=O), 195.3 (2C, >=O). Anal.calc.

for C40H37O6Sb: C, 65.32, H, 5.07, Found: C, 65.30, H, 5.06.

Bis (3-(2, 3-dimethoxyphenyl)acrylato)(triphenyl)antimony(V) (12A)


yield 82%, m.p=156˚C. FTIR(cm-1) 3021(m) (C-Haromatic), 2983(m), 2944(m) &

2888(m) (C-Haliphatic), 1699(s, broad) (C=O), 1597(m) 1581(m), 1483(s), 1464(m),

1456(m), 1442(m), 1426(s), 1320(s), 1298(m), 1267(s)(C-O), 1232(m), 1200(s),

1172(m), 1089(m), 1056(s), 1003(s), 972(s), 940(m), 898(m), 821(m), 807(m), 760(s),

732(m), 569(m)(Sb-C), 550(m), 522(m), 519(m), 459(m), 448(m)(Sb-O).

1HNMR (CDCl3) δ 3.87 (s, 6H, -OCH3), 3.89 (s, 6H, -OCH3), 6.36 (d, 2H, 3J=12Hz,

-CH=CH-Ph), 6.89 (d, 2H, 3J=8.1Hz, ArH), 7.04 (t, 2H, 3J=8.1Hz, ArH), 7.12 (d, 2H,

3J=8.1Hz, ArH), 7.51-7.56 (m, 9H, ArH), 7.85 (d, 2H, 3J=12Hz, -CH=CH-Ph),

8.12 (dd, 6H, 3J=7.8Hz, 4J=2.4Hz, ArH). 13CNMR (CDCl3) δ 55.8 (2C, -OCH3), 61.2

(2C, -OCH3), 113.4(2C), 119.1(2C), 122.3(2C), 124.1(3C), 128.1(2C), 129.3(6C),

131.2(3C), 134.2(6C), 137.7(2C), 38.2(3C, ipso-C), 148.2(2C), 153.2(2C), 171.0 (2C,

>=O). Anal.calc. for C40H37O8Sb: C, 62.60, H, 4.86, Found:

C, 62.58, H, 4.85.

Bis (2, 6-difluorobenzoato)(triphenyl)antimony(V) (13A)

Stoichiometric amounts were calculated as for 12A. Colourless solid, Final yield

84%, m.p.145-146 ˚C, FTIR (cm-1) 3120 (w) & 2930(s) (C-Haromatic), 1630(s) (C=O),

1560(w), 1490(s), 1420(m),1370(w), 1310(m), 1288(s)(C-O), 1270(w), 1140(m),

1020(m), 920(m), 810(m), 770(m), 740(m), 690(m), 570(w)(Sb-C). 526(m), 510(m),

447(m)(Sb-O), 1HNMR(CDCl3) δ 7.44 (t, 3H, ArH, 3J=7.2Hz), 7.56-7.59 (m, 8H,

ArH), 7.80 (d, 4H, ArH,3J=7.2Hz), 8.12 (dd, 6H, ArH,3J=7.2Hz, 4J=2.4Hz), 13CNMR

(CDCl3) δ 128.3 (4C), 129.7 (6C), 132.1 (2C), 131.7 (2C), 133.7 (6C), 134.8 (4C),

135.5 (2C), 136.9 (3C, ipso-C), 167.5 (2C, Carbonyl), Anal. calcd. for C32H21F4O4Sb

(667.26): C, 57.60, H, 3.17, Found: C, 57.57, H, 3.16.

36

Bis (2, 5-dichlorobenzoato)(triphenyl)antimony(V) (14A)


yield 84%, m.p.=160-165˚C. FTIR(cm-1) 3092(m) & 3078(m) (C-Haromatic), 1675(s)

(C=O), 1583(m), 1565(m), 1464(m), 1436(m), 1409(m), 1372(m), 1295(s)(C-O),

1272(m), 1264(m), 1216(m), 1182(m), 1153(m), 1112(s), 1052(m), 901(m), 856(s),

825(s), 784(m), 737(m), 666(m), 616(m), 583(m)(Sb-C), 529(m), 512(m), 444(m)

(Sb-O), 1HNMR (CDCl3) δ 7.46 (t, 3H, ArH, 3J=7.8Hz), 7.54-7.61 (m, 8H, ArH), 7.78

(m, 4H, ArH, 3J=7.2Hz), 8.10 (dd, 6H, ArH, 3J=7.2Hz, 4J=2.4Hz), 13CNMR (CDCl3)

δ 128.3 (3C), 129.7 (6C), 130.4(2C), 131.6 (2C), 131.8 (2C), 132.3(2C), 133.7 (6C),

134.8 (2C), 135.5 (2C), 136.9 (3C, ipso-C), 167.5 (2C, 2C, carbonyl),

Anal. calcd. for C32H21Cl4O4Sb: C, 52.43, H, 2.89, Found: C, 52.40, H, 2.87,

Bis(4-ethoxybenzoato)(triphenyl) antimony(V) (15A)


yield 82%, m.p.=156˚C. FTIR (cm-1) 3264(m), 2984(m) & 3080(m) (C-Haromatic),

2941(m)& 2902(m) (C-Haliphatic), 1738(s) (C=O), 1604(s), 1582(s), 1488(s),1474(s)

1460(s), 1401(s), 1363(s), 1298(s)(C-O), 1239(s), 1226(s), 1164(s), 1128(s), 1113(m),

1089(m), 1076(m), 1039(s), 1030(s), 924(m), 904(m), 864(m), 817(m),

756(s), 687(m), 666(m), 642(m), 613(w), 607(m), 578(m)(Sb-C), 568(m), 548(m),

518(m), 514(m), 455(m), 458(m)(Sb-O). 1HNMR (CDCl3) δ 1.45 (t, 6H, 3J=12Hz, O-

CH2-CH3), 3.98(q, 4H, 3J=20Hz, -O-CH2-CH3), 6.79 (d, 4H, 3J=7.5Hz, ArH), 7.36-

7.42(m, 9H, ArH), 7.88 (d, 4H, 3J=8.1Hz, ArH), 8.04 (dd, 6H, 3J=8.1Hz,

4J=2.4Hz, ArH). 13CNMR(CDCl3) δ 14.5 (2C, -O-CH2-CH3), 63.5 (2C,-O-CH2CH3),

113.7(4C), 129.4(2C), 129.4(6C), 130.9(3C), 131.2(4C), 131.8(6C), 138.4(3C, ipso-

C), 162.1 (2C, C-O-CH2-CH3), 170.1(2C, >=O). Anal.calc. for

C36H33O6Sb: C, 63.27, H, 4.87, Found: C, 63.26, H, 4.85

Bis (3-acetoxybenzoato)(triphenyl)antimony(V) (16A)

Stoichiometric amounts were calculated as for 15A. white crystalline solid, Final yield

84%, m.p.=137˚C. FTIR (cm-1)3005(m) (C-Haromatic), 2891(m) & 2836(m) (CHaliphatic),

37

1685(s) (C=O), 1601(s), 1504(m), 1432(s), 1379(m), 1318(m), 1290(s)(CO), 1221(s),

1202(s), 1168(s), 1123(m), 1104(m), 1098(w), 1017(m), 921(s), 860(s),

825(s), 793(w), 757(s), 701(s), 671(m), 581(w)(Sb-C), 547(m), 501(m), 455(m)(Sb-

O). 1HNMR (CDCl3) δ 2.29 (s, 6H, -C=O-CH3), 7.20 (d, 2H, 3J=7.2Hz, ArH), 7.37 (t,

2H, 3J=7.2Hz, ArH), 7.41-7.44 (m, 9H, ArH), 7.59 (s, 2H, ArH), 7.76 (d, 2H,

3J=7.2Hz, ArH), 8.03 (dd, 6H, 3J=7.2Hz, 4J=1.2Hz, ArH). 13CNMR (CDCl3)δ

21.1(2C, -CH3), 125.4(2C), 127.4(2C), 128.9(2C), 130.0(6C), 132.0(3C), 133.8(6C),

134.0(2C), 134.4(2C), 137.6(3C, ipso-C), 150.4(2C), 169.0 (2C, >=O), 169.4 (2C,

>=O). Anal.calc. for C36H29O8Sb: C, 60.78, H, 4.11, Found: C, 60.74, H, 4.09.

Bis (4-methoxycinnamato)(triphenyl)antimony(V) (17A)


yield 79%, m.p.=147˚C. FTIR (cm-1) 3057(m) (C-Haromatic), 2902(m) & 2844(m)

(CHaliphatic), 1664(s, broad) (C=O), 1629(s), 1614(m), 1584(m), 1512(m),

1464(m),1444(m) 1358(m), 1318(m), 1313(m), 1265(s)(C-O), 1244(s), 1209(m),

1160(m), 1136(s), 1026(s), 979(m), 950(m), 939(m), 866(m), 858(m), 818(m),

762(m), 691(m), 611(m), 605(m), 571(m)(Sb-C), 558(m), 506(m), 502(m),

450(m)(Sb-O). 1HNMR (CDCl3) δ 3.80 (s, 6H, -OCH3), 6.14(d, 2H, 3J=15.6Hz,

CH=CH-), 6.77 (d, 4H, 3J=8.1Hz, ArH), 7.29(d, 4H, 3J=8.4Hz, ArH), 7.33-7.49(m,

11H, ArH, -CH=CH-Ph), 8.01(dd, 6H, 3J=8.1Hz, 4J=2.4Hz, ArH). 13CNMR (CDCl3)δ

55.3(2C, -OCH3), 114.1(6C), 125.3(2C, -CH=CH-), 127.6 (2C, -CH=CH), 128.2(4C),

129.0(6C), 131.1(4C), 137.8(2C), 138.4(2C), 139.0(3C, ipso-C), 143.1(3C),

171.2(2C, >=O). Anal.calc. for C38H33O6Sb: C, 64.52, H, 4.70, Found:

C, 64.49, H, 4.69.

Bis (2-ethoxybenzoato)(triphenyl)antimony(V) (18A)


yield 82%, m.p.=156-157˚C. FTIR (cm-1) 3261(m) & 3078(m) (C-Haromatic), 2980(m)

& 2942(m) (C-Haliphatic), 1739(s) (C=O), 1601(s), 1578(s), 1484(s), 1478(s) 1460(s),

1405(s), 1359(s), 1294(s) (C-O), 1239(s), 1221(s), 1162(s), 1125(s), 1109(m),

38

1088(m), 1075(m), 1030(m), 928(m), 905(m), 868(m), 813(m), 751(s), 681(m),

666(m), 640(m), 610(w), 605(m), 576(m), 569(m) (Sb-C), 545(m), 513(m), 512(m),

456(m)(Sb-O). 1HNMR (CDCl3) δ 1.45 (t, 6H, 3J=12Hz, -O-CH2-CH3), 3.98(q, 4H,

3J=20Hz, -O-CH2-CH3), 6.79 (d, 4H, 3J=7.5Hz, ArH), 7.36-7.42(m, 9H, ArH), 7.88

(d, 4H, 3J=8.1Hz, ArH), 8.04 (dd, 6H, 3J=8.1Hz, 4J=1.2Hz, ArH). 13CNMR (CDCl3)

δ 13.9 (2C, -O-CH2-CH3), 66.5 (2C, -O-CH2-CH3), 113.7(4C), 129.4(2C), 129.4(6C),

131.1(3C), 131.2(4C), 131.8(6C), 133.8(2C), 138.4(3C, ipso-C), 162.1 (2C),

170.1(2C, >=O). Anal.calc. for C36H33O6Sb: C, 63.27, H, 4.87, Found: C,

63.26, H, 4.85

2.3.3. Synthesis of Tris(p-tolyl)antimony(V) dicarboxylates (1B-10B)

The sodium/potassium salt of the carboxylic acid (0.01mol) and organoantimony(V)

(0.005mol) were added in 75 ml of toluene, and stirred for 8-10 hours. The

sodium/potassium halide salt formed was removed by filtration and solvent was

removed under low pressure. The product obtained was dissolved in dichloromethane

and kept under slow evaporation in semi sealed bottles for crystallization. Toluene

was distilled over sodiumbenzophenone ketyl and used fresh when required.

2.3.3.1 Synthesis and characterization data of (1B-10B)

Tris(p-tolyl)bis(4-methylbenzoato)antimony(V) (1B)

The stoichiometric quantities used was 1.59g (0.01 mol) potassium salt of

4methylbenzoic acid and 2.75g (0.005 mol) tris(p-tolyl)antimony(V)dibromide.

Colourless solid, Final yield 82%, m.p.214-215˚C, FTIR(cm-1) 3023 (C-Haromatic) ),

2920 (C-Haliphatic), 1632 (C=O), 551 (Sb-C), 481 (Sb-O), 1HNMR (CDCl3) δ 2.45(s,

15H, -CH3), 7.22(d, 4H, ArHd=d', 3J=8.1Hz), 7.36(d, 6H, ArHb=b',

3J=8.1Hz), 7.95

(d, 4H, ArHc=c', 3J=8.1Hz), 8.11 (d, 6H, ArHa=a',

3J=8.1Hz), 13CNMR(CDCl3) δ

21.6(2C, -CH3), 128.8(4C), 130.0(4C), 130.3(6C), 130.4(2C), 133.7(6C), 134.8(3C),

141.5(3C), 141.5(3C, ipso-C), 142.6(2C), 170.1 (2C, carbonyl C); Anal. calcd. for

C37H35O4Sb: C, 66.78, H, 5.30, Found: C, 66.74, H, 5.26

39

Scheme 3. Synthesis of Tris(p-tolyl)antimony(V) dicarboxylates (1B-10B)

Bis(2-(phenylamino)benzoato)tris(p-tolyl)antimony(V) (2B)

Stoichiometric amounts were calculated as for 1B. Final yield 83%, Colourless solid,

m.p.165-166˚C, FTIR(cm-1) 3250 (-NH),3210 (C-Haromatic), 2921 (C-Haliphatic),

1635(C=O), 562 (Sb-C), 484 (Sb-O), 1H NMR (CDCl3) δ 2.44 (s, 9H, -CH3), 6.78(t,

40

2H, ArHe, J=7.2Hz), 7.09 (t, 2H, ArHg, J=7.2Hz), 7.19 (d, 4H, ArHc=c’, J=7.8Hz),

7.29-7.39 (m,16H, ArHb=b’, d=d’, f,h,i), 8.08 (d, 6H, ArHa=a', J=7.8Hz), 9.57(s, 2H, -NH-

), 13C NMR (CDCl3) δ 21.6 (3C, -CH3), 113.8 (2C), 115.3 (2C), 116.9(2C), 121.9(4C),

122.8(3C), 129.1(4C), 131.0(6C), 132.7(2C), 133.2(2C), 133.8(6C),134.6(2C).141.4

(2C), 141.5(3C), 144.4 (3C, ipso-C), 172.0 (2C, 2C, carbonyl), Anal. calcd. for

C47H41N2O4Sb: C, 68.88, H, 5.04, N, 3.42 Found: C, 68.84, H, 5.01, N, 3.45

Bis(3,5-dichlorobenzoato)tris(p-tolyl)antimony(V) (3B)

Stoichiometric amounts were calculated as for 2B. Final yield 83%,Colourless solid,

m.p.151-153˚C, FTIR(cm-1) 3070 (C-Haromatic), 2910 (C-Haliphatic), 1638 (C=O),740

(C-Cl), 579 (Sb-C), 485 (Sb-O), 1H NMR (CDCl3) δ 2.437 (s, 9H, -CH3), 7.38 (d,

6H, ArHb=b’,J= 8.1Hz), 7.44 (s, 2H, ArHe), 7.80 (s, 4H, ArHc=c’), 7.99 (d, 6H, ArHa=a’,

J=8.1Hz), 13C NMR (CDCl3) δ 21.6 (3C, -CH3), 128.3 (4C), 130.4 (6C), 131.7(2C),

133.2(2C), 133.6(6C), 134.7(4C), 135.9(2C), 142.0 (3C, ipso-C), 167.2 (2C, 2C,

carbonyl), Anal. calcd. for C35H27Cl4O4Sb: C, 54.23, H, 3.51, Cl,

18.29Found: C, 54.20, H, 3.48, Cl, 18.25

Bis(propanoato)tris(p-tolyl)antimony(V) (4B)



(Sb-C), 485 (Sb-O), 1H NMR (CDCl3) δ 2.40 (s, 9H, -CH3), 0.94 (t, 6H, CH3β-CH2-,

ArH, J=7.5Hz), 2.12 (q, 4H, CH3-CH2α-, J=7.5Hz), 7.29 (d, 6H, ArHb=b’, J=7.8Hz),

7.86 (d, 6H, ArHa=a’, J=8.4Hz), 13C NMR (CDCl3) δ 9.82 (2C, -CH2-CH3), 21.5 (3C,

-CH3), 29.1 (2C, CH3-CH2-), 129.8 (6C), 133.7(6C), 135.2(3C), 141.1 (3C, ipso-C),

178.3 (2C, 2C, carbonyl) Anal. calcd. for C27H31O4Sb: C, 59.91, H, 5.77, Found: C,

59.88, H, 5.72

Bis(nicotinato)tris(p-tolyl)antimony(V) (5B)


m.p.181-183˚C, FTIR(cm-1) 3035, 3025(C-Haromatic), 2919(C-Haliphatic),

1638(C=O),1587(C-N), 557(Sb-C), 484(Sb-O), 1H NMR (CDCl3) δ 2.39 (s, 9H,

41

CH3), 7.27(t, 2H, pyridyl He, J=5.1Hz), 7.35(d, 6H, ArHb=b', J=8.1Hz), 8.02 (d, 6H,

ArHa=a', J =8.1Hz), 8.16 (dt, 2H, pyridylHf, 1J=8.1Hz, 2J=1.8Hz), 8.66 (dd, 2H,

pyridylHd, 1J=6.6Hz, 2J=1.8Hz), 9.16(sd, 2H, pyridylHc,

2J=1.2Hz,), 13C NMR

(CDCl3) δ 21.6 (3C, -CH3), 123.0, 128.6, 130.4 (4C), 133.2, 133.6 (6C), 137.5, 141.9

(3C, ipso-C), 151.3 (N-C), 152.4 (N-C), 168.2 (2C, 2C, carbonyl), Anal. calcd. for

C33H29N2O4Sb: C, 61.99, H, 4.57, N, 4.38 Found: C, 61.65, H, 4.48, N, 4.51

Bis((S)-2-Amino-3-(4-imidazolyl)propionato)tris(p-tolyl)antimony(V) (6B)


m.p.211-212˚C, FTIR(cm-1) 3438, 3412 (C-NH2, -NH-), 3100 & 3082 (C-Haromatic),

3020 & 2939 (C-Haliphatic), 1646 (C=O), 564(Sb-C), 475 (Sb-O), 1H NMR (CDCl3) δ

2.39 (s, 9H, -CH3), 2.82(m, broad, -CH2-), 4.20(t, 1H, -CH-), 5.11(s, 2H, -NH2),

7.66(s, 1H, -CHc-), 7.34(d, 6H, ArH), 7.74 (d, 6H, ArH),8.33(s, 1H, -CHd-), 12.68 (s,

1H, -NH-), 13C NMR (CDCl3) δ 21.5 (3C, -CH3), 29.0(2C, -CH2-), 57.1(2C, -CH-),

110.3(6C), 119.9(2C), 120.7(6C), 128.9(3C), 133.2(2C), 138.1(2C), 157.5 (3C,

ipsoC), 176.6 (2C, 2C, carbonyl), Anal. calcd. for C33H37N6O4Sb: C, 56.34, H, 5.30,

N, 11.95 Found: C, 56.31, H, 5.29, N, 11.97

Bis(o-methoxyphenylacetato)tris(p-tolyl)antimony(V) (7B)



(Sb-C), 480 (Sb-O), 1H NMR (CDCl3) δ 2.39 (s, 9H, CH3), 3.67(s, 4H, -CH2-),

3.84 (s, 6H, -OCH3), 6.90-6.99 (m, 4H, ArHc,f), 7.21- 7.33(m, 4H, ArHd,e), 7.17(d, 6H,

ArHb=b', J =8.1Hz), 7.39 (d, 6H, ArHa=a', J =8.1Hz), 13C NMR (CDCl3) δ 21.6 (3C, -

CH3), 45.1 (2C, -CH2-), 55.4 (2C, -OCH3), 110.1(6C), 120.5(6C), 123.3, 128.6(3C),

129.6, 129.7, 131.1(3C), 134.0, 136.2, 157.6 (3C, ipso-C), 178.0 (2C, carbonyl), Anal.

calcd. for C39H39O6Sb: C, 64.57, H, 5.42, Found: C, 64.53, H, 5.39

Bis(p-methoxyphenylacetato)tris(p-tolyl)antimony(V) (8B)


m.p.91-92˚C, FTIR(cm-1) 2930 (C-Haromatic), 2835 (C-Haliphatic), 1640 (C=O), 545 (Sb-

42

C), 486 (Sb-O), 1H NMR (CDCl3) δ 2.41 (s, 9H, CH3), 3.39(s, 4H, -CH2-), 3.84 (s,

6H, -OCH3), 6.79 (d, 4H, ArH, J=9.0Hz), 7.05 (d, 4H, ArH, J=8.7Hz), 7.22 (d, 6H,

ArH, J=9.0Hz), 7.71(d, 6H, ArH, J=8.1Hz), 13C NMR (CDCl3) δ 21.5 (3C, CH3), 42.5

(2C, -CH2-), 55.3 (2C, -OCH3), 113.5(4C), 113.9(2C), 127.8(3C), 129.9(6C),

130.3(4C), 133.7(6C), 141.2 (3C, ipso-C), 158.2(2C, -OCH3), 175.1 (2C, carbonyl

C), Anal. calcd. for C39H39O6Sb: C, 64.57, H, 5.42, Found: C, 64.52, H, 5.39

Tris(p-tolyl)bis(m-chlorophenylacetato) anitmony(V) (9B)

Stoichiometric amounts were calculated as for 8B. White solid, Final yield 90%,

m.p, 152-153 ˚C, FTIR(cm-1) 3050(C-Haromatic), 2928(C-H aliphatic), 1635(COOasym),

562(Sb-C), 477(Sb-O), 1HNMR(CDCl3) δ 2.43(s, 9H,-CH3), 3.35(s, 4H, -CH2-),

7.11(dd, 2H, 3J=7.5Hz, 4J=3.1Hz, ArH), 7.28-7.34(m, 2H, ArH), 7.38(d, 6H,

3J=7.5Hz, ArH), 7.45-7.54(m, 2H, ArH), 7.58(d, 2H,

3J=7.5Hz, ArH), 8.10(d, 6H, 3J=7.1Hz, ArH), 13CNMR(CDCl3) δ 21.8(3C, CH3),

43.5(2C, -CH2-), 114.2(2C), 117.3(2C), 123.2(2C), 130.2(2C), 130.4(6C),

130.6(6C), 135.1(2C), 135.4(2C), 142.6(3C), 146.2(3C, ipso-C), 170.0(2C,

>C=O), Anal.calcd. C37H33Cl2O4Sb: C, 60.52, H, 4.53, Found: C, 60.50, H, 4.52.

Tris(p-tolyl)bis(m-bromophenylacetato) anitmony(V)(10B)

Stoichiometric amounts were calculated as for 9B. Final yield 87%, m.p, 158-159

˚C, FTIR(cm-1) 3046 (C-Haromatic), 2926 (C-H aliphatic), 1634 (COOasym), 565 (SbC), 476

(Sb-O), 1HNMR(CDCl3) δ 2.43(s, 9H,-CH3), 3.36(s, 4H, -CH2-), 7.12(dd,

2H, 3J=7.5Hz, 4J=3.1Hz, ArH), 7.32-7.35(m, 2H, ArH), 7.38(d, 6H, 3J=7.5Hz, ArH),

7.49-7.54(m, 2H, ArH), 7.62(d, 2H, 3J=7.5Hz, ArH), 8.14(d, 6H,

3J=7.1Hz, ArH), 13CNMR(CDCl3) δ 21.6(3C, -CH3), 43.6(2C, -CH2-), 114.4(2C),

115.8(2C), 124.4(2C), 128.2(2C), 132.2(6C), 132.8(6C), 134.0(2C), 136.8(2C),

142.8(3C), 144.6(3C, ipso-C), 170.0(2C, >C=O), Anal.calcd. C37H33Br2O4Sb: C,

53.98, H, 4.04, Found: C, 53.97, H, 4.01.

43

2.3.4. Synthesis of Tris(2,5-dimethylphenyl) antimony(V)dicarboxylates (1C20C)

The sodium/potassium salt of the carboxylic acid (0.01mol) and organo-antimony (V)

(0.005mol) were added in 75 ml of toluene, and stirred for 8-10 hours. The

sodium/potassium halide salt formed was removed by filtration and solvent was

removed under low pressure. The product obtained was dissolved in dichloromethane

and kept under slow evaporation in semi sealed bottles for crystallization. Toluene

was distilled over sodiumbenzophenone ketyl and used fresh when required.

2.3.4.1 Synthesis and characterization data of (1C-20C)

Bis(o-methoxybenzoato)tris(2,5-dimethylphenyl) antimony (V) (1C)

Quantities used were 1.90 g (0.01 mol) potassium salt of o-methoxy benzoic acid and

2.98 g (0.005 mol) tris(2,5-dimethylphenyl)antimony (V) dibromide. White

crystalline solid, Final yield 86%, m.p.=112-114˚C. FTIR(cm-1) 3143(w), 3080(w),

2923(m), 2860(m), 1661(s), 1597(m), 1485(w), 1243(s), 1105(m), 1080(m),

1018(m), 850(w), 753(s), 700(w), 657(m), 563(m), 440(s), 316(w), 290(s), 3143 (C-

Haromatic), 2923, 2860 (C-Haliphatic), 1661(C=O), 563(Sb-C), 440(Sb-O), 1HNMR

(CDCl3) δ 2.34 (s, 9H, -CH3), 2.54(s, 9H, -CH3), 3.64(s, 6H. -OCH3), 6.79-6.84(m,

4H, ArH), 7.21-7.24(m, 6H, ArH), 7.25(d, 2H, 3J=4.5Hz, ArH), 7.47(dd, 2H,

3J=7.8Hz, 4J=1.8Hz, ArH), 8.26(s, 3H, ArH), 13CNMR (CDCl3) δ 21.2 (3C, -CH3),

22.9(3C, -CH3), 55.4(2C, -OCH3), 131.2(3C), 131.3(2C), 131.7(2C), 132.2(3C),

133.7(2C), 134.7(2C), 135.5(3C), 135.9(3C), 138.9(2c), 139.1(3C), 139.3(3C),

158.4(2C, >C-O-CH3), 168.4(2C, >=O). Anal.calc. for C40H41O6Sb: C, 64.97, H,

5.59, Found: C, 64.95, H, 5.57.

44

Scheme 4. Synthesis of tris(2,5-dimethylphenyl)antimony(V) dicarboxylates

(1C20C)

45

Tris(2,5-dimethylphenyl)bis(3-methoxybenzoato) antimony (V) (2C)

Stoichiometric amounts were calculated as for 1C. White crystalline solid, Final

yield 81%, m.p.=145-146°C. FTIR(Powder cm-1) 3228 (w), 2926(m), 1651(s),

1588(m), 1459(m), 1292(s), 1109(m), 1035(m), 907(w), 761(s), 600(m), 550(m),

445(s), 294(s), 3228 (C-Haromatic), 2929(C-Haliphatic), 1651 (C=O), 550(Sb-C),

445(Sb-O). 1HNMR (300MHz, CDCl3) δ 2.38(s, 9H, -CH3), 2.54(s, 9H, -CH3),

3.75(s, 6H, -OCH3), 6.98(dd, 2H, 3J=8.1Hz, 4J=2.7Hz, ArH), 7.22(t, 2H, 3J=7.8Hz,

ArH), 7.26(s, 6H, ArH), 7.36-7.41(m, 4H, ArH), 8.25(s, 3H, ArH). 13CNMR

(75MHz, CDCl3) δ 21.1(3C, -CH3), 21.2(3C, -CH3), 55.2(2C, -OCH3 ), 114.0(2C),

118.2(2C), 122.3(2C), 128.8(3C), 131.4(3C), 132.1(3C), 135.4(3C), 135.5(2C),

136.2(3C), 138.6(2C), 138.8(3C), 159.2(2C, >C -OCH3), 168.1 (2C, >=O).

Anal.calc. for C40H41O6Sb: C, 64.97, H, 5.59, Found: C, 64.95, H, 5.57.

Tris(2,5-dimethylphenyl) bis(4-methoxybenzoato) antimony (V) (3C)

Stoichiometric amounts were calculated as for 2C. White crystalline solid, Final yield

78%, m.p.=114-118˚C. FTIR(cm-1) 3048(w), 2924(s), 2675(w), 1645(s),

1603(s), 1497(m), 1294(s), 1252(s), 1160(s), 1123(w), 1025(s), 845(m), 776(m),

694(m), 617(s), 600(w), 442(m), 289(s), 3048 (C-Haromatic), 2924(C-Haliphatic), 1645

(C=O), 600(Sb-C), 442(Sb-O). 1HNMR (CDCl3) δ 2.38 (s, 9H, -CH3), 2.53(s, 9H,

CH3), 3.82(s, 6H, -OCH3), 6.79(d, 4H, 3J=8.7Hz, ArH), 6.97(d, 3H,3J=8.7Hz, ArH),

7.78(d, 4H, 3J=8.7Hz, ArH), 8.10(d, 3H, 3J=8.7Hz, ArH), 8.26(s, 3H, ArH).

13CNMR (CDCl3) δ21.2 (3C, -CH3), 22.9(3C, -CH3), 55.3(2C, -OCH3), 113.0(4C),

126.6(2C), 131.3(3C), 131.6(4C), 131.9(3C), 135.5(3C), 136.1(3C), 138.8(3C),

138.9(3C), 163.8(2C, CH3-O-Ph), 168.5(2C, >=O). Anal.calc. for C40H41O6Sb: C,

64.97, H, 5.59, Found: C, 64.96, H, 5.58.

Tris(2, 5-dimethylphenyl) Bis(3, 4, 5-trimethoxy benzoato) antimony (V) (4C)

Stoichiometric amounts were calculated as for 3C. Colorless solid, Final yield 78%,

m.p.=168-170°C. FTIR(cm-1) 3042(m), 2934(m), 2910(w), 1653(s), 1585(s),

1497(m), 1460(m), 1411(s), 1328(s), 1226(s), 1123(s), 1006(m), 940(m), 818(w),

46

4(m), 727(m), 540(m), 440(m), 319(s), 285(s), 3042 (C-Haromatic), 2934 & 2910(C-

Haliphatic), 1653 (C=O), 550(Sb-C) 440(Sb-O). 1HNMR(CDCl3) δ 2.37 (s,

9H, -CH3), 2.56(s, 9H, - CH3), 3.78(s, 12H, -OCH3), 3.84(s, 6H, -OCH3), 7.09(s, 4H,

ArH), 7.26(s, 6H, ArH), 8.22(s, 3H, ArH). 13CNMR(CDCl3) δ21.2(3C, -CH3),

22.9(3C, -CH3), 55.9(4C, -OCH3), 60.8(2C, -OCH3), 106.8(4C), 131.3(3C),

132.2(3C), 133.4(3C), 135.3(3C), 136.3(3C), 138.4(3C), 140.8(2C), 152.5(4C, -

COCH3), 152.9(2C, -C-OCH3), 167.6 (2C, >=O). Anal.calc. for C44H49O10Sb: C,

61.48, H, 5.75, Found: C, 61.46, H, 5.74

Tris(2,5-dimethylphenyl)bis(phenyl acetato) antimony (V) (5C)

Stoichiometric amounts were calculated as for 4C. White crystalline solid, Final yield

86%, m.p=110-112˚C. FTIR(cm-1) 3030(m), 2921(m), 2360(m), 1665(s), 1490(m),

1447(m), 12168(s), 1441(s), 1029(m), 931(m), 813(s), 718(s), 643(s),

561(m), 438(s), 289(s), 3030 (C-Haromatic), 2921(C-Haliphatic), 1665 (C=O), 561(SbC),

438(Sb-O). 1HNMR (CDCl3) δ 2.31 (s, 9H, -CH3), 2.32(s, 9H,-CH3), 3.33(s, 4H, -

CH2-), 6.97(dd, 4H, 3J=5.7Hz, 4J=2.1Hz, ArH), 7.13-7.25(m, 12H, ArH), 7.81(s,

3H, ArH). 13CNMR (CDCl3) δ21.1 (3C, -CH3), 22.7(3C, -CH3), 44.1(2C, -CH2-),

126.2(3C), 128.1(4C), 129.2(4C), 131.3 (3C), 131.7(3C), 135.0(3C), 135.7(3C),

135.9(2C), 138.8(3C), 138.9(2C), 173.4 (2C,>=O). Anal.calc. for C40H41O4Sb: C,

67.90, H, 5.84, Found: C, 67.88, H, 5.85

Tris(2,5-dimethylphenyl)bis(Phenoxyacetato) antimony (V) (6C)

Stoichiometric amounts were calculated as for 5C. Final yield 82%, white crystalline

solid, m.p.=142˚C. FTIR(cm-1) 3029(w), 2926(m), 1637(s), 1447(s), 1035(m), 808(s),

556(m), 435(s), 320(s), 286(s), 3029 (C-Haromatic), 2926 (C-Haliphatic), 1637, (C=O),

556(Sb-C), 435(Sb-O).1HNMR (CDCl3) δ 2.31(s, 9H, CH3), 2.37(s, 9H, -CH3), 4.38(s,

4H,-OCH2-), 6.93(dd, 4H, 3J=5.7Hz, 4J=1.8Hz, ArH), 7.09-7.24(m, 12H, ArH),

7.78(s, 3H, ArH). 13CNMR (CDCl3) δ21.1 (3C, CH3), 22.7(3C, -CH3), 66.3(2C, -

CH2-), 125.9(3C), 127.8(4C), 128.4(4C), 131.1(3C), 132.1(3C), 134.8(3C),

47

134.9(3C), 135.7(2C), 138.7(3C), 156.4(2C, -OCPh), 170.0(2C, >=O). Anal.calc. for

C40H41O6Sb: C, 64.97, H, 5.59, Found: C, 64.96, H, 5.58.

Tris(2,5-dimethylphenyl)bis(dimethylphenylaminobenzoato) antimony (V) (7C)

Stoichiometric amounts were calculated as for 6C. Final yield 78%, Colorless solid,

m.p.=156-157˚C. FTIR(cm-1) 3259(m), 3010(m), 2922(m), 2359(m), 1631(s),

1578(s), 1499(s), 1448(m), 1329(m), 1252(s), 1147(m), 1010(w), 750(m), 561 (m),

435(s), 322(s), 286(s), 3259(-NH-), 3010 (C-Haromatic), 2922(C-H aliphatic), 1631 (C=O),

561(Sb-C), 435(Sb-O). 1HNMR (CDCl3) δ 1.98 (s, 6H, -CH3), 2.31(s, 6H, CH3), 2.36

(s, 9H. -CH3), 2.59(s, 9H, -CH3), 6.56(t, 2H, 3J=8.1Hz, ArH), 6.67(d, 2H, 3J=7.8Hz,

ArH), 6.97-7.15(m, 8H, ArH), 7.16-7.25(m, 6H, ArH), 7.76(dd,

2H,3J=8.1Hz,4J=1.8Hz, ArH), 8.23(s, 3H, ArH), 9.29(s, 2H, -NH-), 13CNMR (CDCl3)

δ13.8 (2C, -CH3), 20.6(2C, -CH3), 21.3(3C, -CH3 ), 23.0(3C, -CH3), 112.9(2C),

114.8(2C), 115.4(2C), 123.4(2C), 125.6(2C), 126.2(2C), 131.5(3C), 131.9(3C),

132.3(2C), 132.5(2C), 132.7(2C), 135.5(3C), 136.2(3C), 137.8(2C), 138.8(3C),

138.9(2C), 139.4(2C), 148.9(3C), 170.6 (2C, >=O). Anal.calc. for C54H55N2O4Sb: C,

70.67, H, 6.04, N, 3.05, Found: C, 70.66, H, 6.03, N, 3.06.

Tris(2,5-dimethylphenyl)bis(o-methylbenzoato) antimony (V) (8C)

Stoichiometric amounts were calculated as for 7C. White solid, Final yield 81%,

m.p.=175-176˚C. FTIR(cm-1) 3029(w), 2921(m), 1654(s), 1489(m), 1440(m),

1400(m), 1299(s), 1269(s), 1144(m), 1088(s), 1040(w), 819(m), 745(s), 720(w),

660(m), 557(m), 439(s), 400(m), 345(s), 277(s), 3029 (C-Haromatic), 2921(C-Haliphatic),

1654 (C=O), 557(Sb-C), 439(Sb-O), 1HNMR (CDCl3) δ 2.31 (s, 6H, CH3), 2. 41 (s,

9H, -CH3), 2.55 (s, 9H, -CH3), 6.73-6.85 (m, 4H. ArH), 7.20-7.25(m, 6H, ArH),

7.26(d, 2H, 3J=7.5Hz, ArH), 7.53(dd, 2H, 3J=7.5Hz, 4J=1.8Hz ArH), 8.25(s, 3H,

ArH). 13CNMR (CDCl3) δ21.2 (2C, -CH3), 21.3(3C, -CH3), 22.7(3C, CH3), 125.9(2C),

126.7(2C), 130.2(2C), 132.1(3C), 132.2(2C), 132.8(3C), 133.9(2C), 135.2(3C),

135.8(3C), 136.8(2C), 137.6(3C), 138.4(3C), 167.7 (2C, >=O). Anal.calc. for

C40H41O4Sb: C, 67.90, H, 5.84, Found: C, 67.87, H, 5.83.

Bis(3-methyl benzoato)tris(2,5-dimethylphenyl) antimony (V) (9C)

Stoichiometric amounts were calculated as for 8C. Final yield 76%, white crystalline

material, m.p.=181-183˚C. FTIR(cm-1) 3028(w), 2922(s), 2360(m), 1650(s), 1601(m),

1442(m), 1305(s), 1209(s), 1109(m), 1036(w), 901(w), 790(w),

48

7478(s), 674(m), 568(m), 517(m), 433(s), 323(s), 286(s), 3028 (C-Haromatic), 2922(C-

Haliphatic), 1650 (C=O), 568(Sb-C), 433(Sb-O), 1HNMR (CDCl3) δ 2.32 (s, 6H, CH3),

2.41(s, 9H, -CH3), 2.55(s, 9H, -CH3), 7.17-7.22 (m, 4H. ArH), 7.26(s, 6H, ArH),

7.63(d, 2H, 3J=7.2Hz, ArH), 7.61(s, 2H, ArH), 8.27(s, 3H, ArH). 13CNMR

(CDCl3) δ21.2 (2C, -CH3), 21.3(3C, -CH3), 22.9(3C, -CH3), 126.8(2C), 127.8(2C),

130.5(2C), 130.4(3C), 132.0(3C), 132.2(2C), 133.9(2C), 135.5(3C), 136.1(3C),

137.5(2C), 138.8(3C), 138.9(3C), 168.4(2C, >=O). Anal.calc. for C40H41O4Sb: C,

67.90, H, 5.84, Found: C, 67.92, H, 5.82

Tris(2,5-dimethylphenyl)bis(furoato) antimony (V) (10C)

Stoichiometric amounts were calculated as for 9C. Final yield 77%, white solid,

m.p=144146˚C. FTIR(Powder cm-1) 3137(w), 2922(w), 2360(m), 1642(s), 1571(m),

1476(s), 1389(m), 1312(s), 1225(w), 1177(s), 1122(s), 1006(m), 927(m), 771(s),

563(m), 439(s), 298(s), 279(m), 3137 (C-Haromatic), 2922 (C-Haliphatic), 1642 (C=O),

1177(C-O-C), 563(Sb-C), 439(Sb-O). 1HNMR (CDCl3) δ 2.38 (s, 9H, -CH3), 2.56(s,

9H, -CH3), 6.35(dd, 2H, 3J=3.3Hz, 4J=1.5Hz, Furyl-H), 6.77(dd, 2H, 3J=3.3Hz,

4J=1.6Hz, Furyl-H), 7.18-7.26(m, 8H, ArH+Furyl-H), 8.18(s, 3H, ArH). 13CNMR

(CDCl3) δ 21.2(3C, -CH3), 22.9(3C, -CH3), 11.2(2C), 115.7(2C), 125.3(2C),

128.2(2C), 129.5(3C), 131.4(3C), 135.3(3C), 136.2(3C), 138.3(3C), 144.8(3C),

160.3(2C, >=O). Anal.calc. for C34H33O6Sb: C, 61.93, H, 5.04, Found: C, 61.90, H,

5.04.

Bis(2-thiophene carboxylato)tris(2,5-dimethylphenyl) antimony (V) (11C)

Stoichiometric amounts were calculated as for 10C. Final yield 86%, yellowish

crystalline material, m.p.=165-166˚C. FTIR(cm-1) 3025(w), 2923(m), 2674(m),

1038(s), 1639(s), 1521(m), 1487(m0, 1417(s), 1357(m), 1283(s), 1096(s), 1029(m),

857(m), 758(m), 718(s), 651(m), 532(m), 441(s), 326(m), 292(s), 3025 (C-Haromatic),

2923(C-Haliphatic), 1639 (C=O), 718(C-S), 532(Sb-C), 441(Sb-O). 1HNMR (CDCl3) δ

2.39 (s, 9H, -CH3), 2.56(s, 9H, -CH3), 6.95 (t, 2H, 3J=5.1Hz, Thiophene-H),

7.227.30(m, 6H, ArH), 7.34 (d, 2H,3J=5.1Hz, Thiophene-H),7.47(d, 2H, 3J=3.6Hz,

49

Thiophene), 8.20(s, 3H, ArH). 13CNMR (CDCl3) δ21.1 (3C, -CH3), 22.9(3C, -CH3),

127.4(3C), 130.6(2C), 131.4(3C), 131.8(2C), 132.2(3C), 135.4(3C), 136.3(3C),

138.2(2C), 138.9(3C), 140.5(2C), 164.4(2C, >=O). Anal.calc. for C34H33O4S2Sb: C,

59.05, H, 4.81, S, 9.27, Found: C, 57.00, H, 4.79, S, 9.26

Bis(benzenepropenoato)tris(2,5-dimethylphenyl) antimony (V) (12C)

Stoichiometric amounts were calculated as for 11C. Final yield 74%, White crystalline

solid, m.p.=146-148˚C. FTIR(cm-1) 3027(w), 2922(m), 2360(m), 1647(s),

1610(w), 1500(w), 1480(w), 1279(s), 1205(m), 750(m), 705(m), 567(m), 441(m),

340(w), 293(s), 3027 (C-Haromatic), 2922(C-Haliphatic), 1647 (C=O), 1610(-HC=HC-),

567(Sb-C), 441(Sb-O). 1HNMR (CDCl3) δ 2.31 (s, 9H, -CH3), 2.33(s, 9H, -CH3),

6.37 (d, 2H, 3J=15.9Hz, -CH=CH-Ph), 6.87(dd, 4H, 3J=7.5Hz, 4J=2.5Hz, Ar-H),

7.06-7.24 (m, 14H, Ar-H+CH=CH), 7.78(s, 3H, Ar-H). 13CNMR (CDCl3) δ21.6 (3C,

CH3), 22.3(3C, -CH3), 121.5(2C), 127.8(3C), 128.6(4C), 129.7(2C), 130.1(3C),

130.9(3C), 132.4(3C), 133.5(3C), 134.8(3C), 135.1(2C), 141.4(4C), 143.1(2C),

169.3(2C, >=O) Anal.calc. For C42H41O4Sb: C, 68.96, H, 5.65, Found: C, 68.94, H,

5.64.

. Tris(2,5-dimethylphenyl) bis(2-acetoxybenzoato) antimony (V) (13C)

Stoichiometric amounts were calculated as for 12C. Colorless solid, Final yield

78%, m.p.=120˚C, FTIR(cm-1) 3012 (C-Haromatic), 2923(C-H aliphatic), 1638 (C=O),

561(Sb-C), 451(Sb-O). 1HNMR (CDCl3) δ 2.39(s, 9H, -CH3), 2.56(s, 9H, -CH3),

3.12(s, 6H, -CH3), 6.73(t, 2H, 3J=7.8Hz, Ar-H), 6.84(d, 2H, 3J=8.4Hz, ArH),

7.247.33(m, 8H, Ar-H), 7.55 (d, 2H, 3J=6.3Hz, Ar-H), 8.18(s, 3H, Ar-H). 13CNMR

(CDCl3) δ21.0(2C, -CH3CO-), 21.2(3C,-CH3), 22.8(3C,-CH3), 115.6(2C), 116.5(2C),

118.4(3C), 130.5(2C), 131.7(2C), 132.2(3C), 134.3(3C), 134.9(2C), 135.3(3C),

136.6(3C), 137.7(2C), 138.8(3C), 161.6(2C, >=O), 171.9(2C, >=O) Anal.calc. For

C42H41O8Sb: C, 63.41, H, 5.19, Found: C, 63.40, H, 5.18.

50

Tris(2,5-dimethylphenyl)bis(cyanoacetato) antimony (V) (14C)

Stoichiometric amounts were calculated as for 13C. Final yield 78%, white material,

m.p.=210-211˚C, FTIR(cm-1) 3015(w), 2919(m), 1640(m), 1582(m), 1485(s),

1200(w), 1035(w), 811(s), 790(s), 563(m), 439(s), 285(s), 3015 (C-Haromatic), 2911(C-

Haliphatic), 1640 (C=O), 1582(-CN), 563(Sb-C), 439(Sb-O), 1HNMR (CDCl3) δ 2.31(s,

4H, -CH2-), 2.41(s, 9H, -CH3), 2.53 (s, 9H. -CH3), 7.11-7.24(m, 6H, Ar-H ) 8.11(s,

3H, Ar-H), 11CNMR (CDCl3) δ 21.2 (3C, -CH3), 22.9 (3C, -CH3), 42.7(2C, CH2-),

121.7(2C,-CN), 127.4(3C), 131.7(3C), 132.2(3C), 135.4(3C), 136.3(3C), 138.7(3C),

169.3 (2C, >=O), Anal.calc. C30H31N2O4Sb: C, 59.52, H, 5.16, N, 4.63, Found: C,

59.50, H, 5.15, N, 3.64.

Tris(2,5-dimethylphenyl)bis(oxonato) antimony (V) (15C)

Stoichiometric amounts were calculated as for 14C. Colorless solid, Final yield

78%, m.p.=230-232˚C. FT-IR(cm-1) 3410(s, br), 3019(w), 2919(m), 1637(s), 1488(s),

1470(m), 1382(m), 1035(m), 813(s), 561(m), 458(s), 270(s), 3410(s, br)(OH), 3019

(C-Haromatic), 2919(C-Haliphatic), 1637 (C=O), 561(Sb-C), 458(Sb-O). 1HNMR (CDCl3)

δ 2.30(s, 9H, -CH3), 2.33(s, 9H, -CH3), 7.08-7.24(m, 6H, ArH), 7.95 (s, 4H.-OH),

8.06(s, 3H, ArH). 13CNMR (CDCl3) δ22.1 (3C, -CH3), 23.4(3C, CH3), 126.4(3C),

129.1(3C), 131.6(3C), 132.8(3C), 133.4(3C), 135.7(3C), 161.7(2C), 168.9(2C),

170.4(2C), 173.9(2C, >=O). Anal.calc. for C32H31N6O8Sb: C, 51.29, H, 4.17, N,

11.21, Found: C, 51.29, H, 4.18, N, 11.23.

Tris(2, 5-dimethylphenyl)bis(2-phenylglycinato) antimony (V) (16C)


m.p.=197-198˚C. FTIR(cm-1) 3368(s, br), 3022(w), 2920(m), 1639(m), 1530(m),

1027(m), 809(s), 568 (m), 440(s), 295(s), 3368(-NH2), 3022(C-Haromatic), 2920(C-

Haliphatic), 1639(C=O), 568(Sb-C), 440(Sb-O). 1HNMR (CDCl3) δ 2.38 (s, 9H, -CH3),

6(s, 9H, -CH3), 3.98 (s, 2H, -CH-), 5.09 (s, 4H, -NH-), 7.19(d, 4H, 135.9(2C),

51

136.4(3C), 138.9(3C), 173.5(2C, >=O) Anal.calc. For C40H43N2O4Sb: C, 65.14, H, 5.88,

N, 3.80, Found: C, 65.13, H, 5.87, N, 3.81.

Tris(2,5-dimethylphenyl)bis(indazole-3-carboxylato) antimony (V) (17C)


m.p.=212-214˚C. FTIR(cm-1) 3464 (s,br), 3232(s,br), 3025(w), 2918(m), 2360(m),

1639(s), 1487(m), 1404(m), 1292(m), 1232(m), 1143(m), 1032(m), 811(s), 749(s),

694(m), 435(s), 339(m), 315(m), 278(s), 3232(N-H), 3047(C-H aromatic), 2918 (C-H

aliphatic), 1639 (C=O), 565 (Sb-C), 457(Sb-O). 1HNMR (CDCl3) δ 2.38 (s, 9H, -

CH3), 2.61(s, 9H, -CH3), 6.86 (t, 2H, 3J=6.9Hz, ArH), 7.10-7.34 (m, 10H, ArH),

7.60(t, 2H, 3J=6.9Hz, ArH), 8.01(s, 3H, ArH), 8.28(s, 2H, -NH-). 13CNMR

(CDCl3) δ21.1 (3C, -CH3), 21.2(3C, -CH3), 120.2(2C), 122.6(2C), 124.3(2C),

131.0(2C), 131.8(3C), 132.4(3C), 134.8(3C), 135.4(3C), 136.3(3C), 138.2(2C),

138.4(3C), 138.9(2C), 163.9(2C, -NC), 164.0(2C, >=O). Anal.calc. for

C40H37N4O4Sb: C, 63.26, H, 4.91, N, 7.38, Found: C, 63.23, H, 4.92, N, 7.41.

Bis(indole-2-carboxylato)tris(2,5-dimethylphenyl) antimony (V) (18C)


m.p.=186-188˚C. FTIR(cm-1) 3286(s, br), 3029(w), 2921(m), 1631(s), 1521(m),

1500(w), 1381(m), 1310(m), 1258(s), 1015(m), 780(m), 743(m), 589(m),

561(m), 441(s), 343(s), 291(s), 3286(NH), 3029(C-Haromatic), 2921(C-Haliphatic), 1631

(C=O), 561 (Sb-C), 441(Sb-O). 1HNMR (CDCl3) δ 2.39 (s, 9H, -CH3), 2.63(s, 9H,

CH3), 7.06-7.21 (m, 6H, ArH), 7.31-7.43(m, 6H, ArH), 7.65(d, 2H,3J=7.5Hz, ArH),

7.97(d, 2H, 3J=7.8Hz, ArH), 8.09(s, 3H, ArH), 8.51(s, 2H, -NH-). 13CNMR (CDCl3)

δ21.1 (3C, -CH3), 21.4(3C, -CH3), 120.2(2C), 122.6(2C), 124.3(2C), 131.2(2C),

131.8(3C), 132.4(3C), 134.8(3C), 135.4(3C), 136.3(3C), 136.8(2C), 138.4(2C),

138.7(3C), 139.1(2C), 141.2(2C), 169.2(2C, >=O). Anal.calc. for C42H39N2O4Sb:

C, 66.59, H, 5.19, N, 3.70, Found: C, 66.49, H, 5.17, N, 3.72.

52

Tris(2,5-dimethylphenyl) bis(5-methyl-2-pyrazine carboxylato) antimony (V) (19C)


m.p.=182-184˚C. FTIR(cm-1) 3434(s, br), 2928(w), 2919(m), 1651(s),

1487(s), 1447(w), 1278(s), 1149(s), 1032(s), 812(s), 571(m), 437(s), 292(s),

3028(C-Haromatic), 2919 (C-H aliphatic), 1651 (C=O), 1032(-CN), 571(Sb-C), 437(SbO).

1HNMR (CDCl3) δ 2.36 (s, 6H, -CH3), 2.39(s, 9H, -CH3), 2.67 (s, 9H, -CH3), 7.27 (s,

6H, ArH), 7.75 (s, 3H, ArH), 7.98 (s, 2H, pyrazine-H), 8.45 (s, 2H, pyrazine-H),

13CNMR (CDCl3) δ21.1 (3C, -CH3), 23.4(2C, -CH3), 23.8(3C, -CH3), 131.6(3C),

131.9(3C), 132.4(3C), 133.4(3C), 134.6(2C), 134.8(2C), 136.3(3C), 136.4(3C),

137.5(2C), 140.8(2C), 165.4(2C, >=O), Anal.calc. for C36H37N4O4Sb:

C, 60.77, H, 5.24, N, 7.87, Found: C, 60.73, H, 5.23, N, 7.88.

Tris(2,5-dimethylphenyl) bis((methylthionicotinato) antimony (V) (20C)

Stoichiometric amounts were calculated as for 19C. Final yield 80%, Colorless Solid,

m.p.=174-176˚C. FTIR(cm-1) 3026(w), 2921(m), 2360(m), 1646(s), 1550(m),

1510(m), 1389(s), 1291(s), 1231(w), 1143(m), 1063(m), 813(m), 766(m), 575(m),

450(m), 410(s), 310(s), 299(s), 278(s), 3026(C-Haromatic), 2921 (C-Haliphatic), 1646

(C=O), 766(-C-S), 575(Sb-C), 451(Sb-O). 1HNMR (CDCl3) δ 2.39 (s, 9H, -CH3),

2.41(s, 9H, -CH3), 2.51 (s, 6H, -SCH3), 6.86-6.91 (m, 2H, pyridinyl-H), 7.21-7.27 (m,

6H, ArH), 7.84 (dd, 2H, 3J=7.8Hz, 4J=1.8Hz, pyridinyl-H), 8.28 (s, 3H, ArH), 8.43

(dd, 2H,3J=4.8Hz, 4J=1.8Hz, Pyridinyl-H). 13CNMR (CDCl3) δ13.9 (3C, SCH3),

21.2(3C, -CH3), 23.0(3C, -CH3), 117.8(2C), 127.2(2C), 131.8(3C), 132.3(3C),

134.8(2C), 135.6(3C), 136.3(3C), 138.4(3C), 138.8(3C), 150.5(2C), 161.7(2C),

167.4(2C, >=O). Anal.calc. C38H39N2S2O4Sb: C, 59.00, H, 5.08, N, 3.62, S, 8.29

Found: C, 58.97, H, 5.91, N, 3.63, S, 8.28.

2.3.5. Synthesis of Organoantimony(V) Dicarboxylates (1D-10D), (1E-10E), (1F-10F)

and (1G-10G).

The synthesis of antimonials (1D-10D), (1E-10E), (1F-10F) and (1G-10G) has been

accomplished by using the same methodology as mentioned in 2.3.1 to 2.3.4. The

53

characterization and biological activities data is included as a supplementary material

withis dissertation.

REFERENCES

1. (a)Perrin D. D., Armarego, W. L. F. “Purification of Laboratory Chemicals”, Ed.,

6th, Amsterdam Elsevier/Butterworth-Heinemann 2009, London, New York,

ISBN: 9781856175678. (b) Armarego, W.L.F and Chai, C.L.L., “Purification of

Laboratory Chemicals”, Ed., 5th, Butterworth Heinemann, London, New York,

2003.

2. Altomare et al., J. Appl. Crystallogr., (1999) 32, 115.

3. Sheldrick, G.M., SHELXL97 (1997) University of Göttingen, Germany.

4. Ali, M.I., Rauf, M.K., Badshah, A., Kumar, I., Forsyth, C.M., Junk, P.C.,

Kedzierski, L., Andrews, P.C. Dalton Trans. 2013, 42, 16733-16741.

5. Asghar F., Badshah A., Shah A., M Rauf.K., Ali M.I., Tahir M.N., Nosheen E.,

Zia, R., Qureshi, R., J. Organomet. Chem. 2012, 717, 1-8.

6. Mushtaq, R., Rauf, M.K., Bond, M., Badshah, A., Ali M.I., Nadhman, A.,

Yasinzai, M., Tahir, M.N. Appl. Organometal. Chem. 2016, 30, 465–472.

7. Mushtaq, R., Rauf, M.K., Bolte, M., Nadhman, A., Badshah, A., Tahir, M.N.,

Yasinzai, M., Khan, K.M., Appl. Organometal. Chem.2017, 31, e3606.

8. Rauf, M.K., Shaheen, U., Asghar, F., Badshah, A., Nadhman, A., Azam, S., Ali,

M. I., Shahnaz, G., Yasinzai, M., Arch. Pharm. Chem. Life Sci. 2015, 348, 1-

13.

54

Chapter-1

BIOLOGICAL STUDIES

For the rapid development of drugs, new methodologies have been established to

determine the bioactivities of natural and synthesized compounds. In the field of drug

discovery preliminary screening is very crucial to select the lead candidates and for

further pharmacological evaluation, initial screenings to identify the drug candidates

for secondary and tertiary trials. To cure human, animals and plants from harm full

effects of micro-organism, these screening act as a tool to identify the bioactive

compounds.

3.1. Biological Screening of Some Selected Pentavalent Antimonials

Metal containing compounds have been extensively used in medicine, mainly in the

cure of carcinomas, parasitic diseases; micronutrients based desfunctionings and

inflammatory disorders. The increased progress in modern inorganic based medicinal

chemistry is owing to the redox-active nature of metal and inductive effect of

coordinating ligands. The biomolecules like proteins, DNA and RNA facilitate

binding to metal atoms in inorganic compounds. Due to the diverse bioactivity

potential, significance of metal based drug is increasing [1-3]. Pentavalent antimonials

1 .1.1 Antileishmanial Screening

From the very beginning, antimony based compounds have been practiced clinically

about a 100 years ago for the treatment of parasitic diseases like trypanosomiasis,

schistomiasis and various type of leishmaniasis [4]. In 1913, potassium antimony (III)

tartrate and other antimony III based drugs were baned for the time being due to their

toxic nature and lethal side effects. Potassium antimony (III) tartrate was the

55

have well known therapeutic behaviour. So in this work, we have investigated the anti-

leishmanial and anti-cancer potential of the synthesized pentavalent antimonials.

A very first antimonial drug used against parasitc diseases especially against

leishmaniasis. In 1940s, antimony III drugs were substituted by antimony (V)

compounds like sodium stibogluconate and meglumine antimoniate commercially

known as Pentostam and Glucantime respectively. These antimonials were found to

more active and 10 times less poisonous to humans and animals than trivalent

analogues. The safest nature of pentavalent antimonial chemotherapy is obvious from

the upturn survival rate as reported above 90% [5]. Promastigote stage is considered

best for the initial screening owing to its easy cultivation and for in vitro determination

of anti-leishmanial impact of tested drugs [6]. The leishmanicidal potency of the tested

pentavalent antimonials was assessed by MTT colorimetric assay following

previously described protocols [7] and also delineated below as a reference

“Leishmania tropicakwh 23 promastigotes were cultured in medium-199 along with

culture media of 10% FBS, 100 µg/mL streptomycin. sulphate and 100 IU/mL

penicillin G at ambient temperature. An fraction of 180 µL of promastigotes at

cellularity of 1×106 promastigotes/mL was incubated with 20 µl (20 µg/ml) of tested

drugs (having ≤ 1% DMSO in phosphate buffer saline) in 96 well plate at 24°C for 72

h. 1% DMSO as negative and Amphotericin. B (1 µg/mL) was taken as positive

controls. Before and after the addition of MTT solution (4 mg/mL), incubation is done

at 24°C. The floating was decant off cautiously and then formazan. product was

solubilized in 100 µL of DMSO. Spectral peak was noticed at 541 nm employing plate

photoreader. Three fold dilutions of compounds were used for IC50 determination.

Antileishmanial data of antimonials (V) and their acids-products are described in

Table 4.1. The viability was evaluated by MTT assay whose yellow tetrazolium salt

is reduces to give dark purple-blue formazan assay by mitochondrial enzyme of

targeted cells. Because of formazan cell impermeability, viable cells look purple-blue.

The selected free acids presented lower potency then Sb (V) scaffolds. Activity

meaningfully improved on coordination with aromatic groups bearing antimony (III)

56

precursors.” The increase in population of lipophilic groups around the antimony

centre increases the lipophilicity of the pentavalent. Results of complexes were

insignificantly different from Glucantime/amphotericin B signifying their efficiency

comparable to Glucantime/amphotericin B. Antileishmanial assay results indicated

that a strong association exists between the structural features and the potency of

complexes having variety of substituents at various positions of antimonials exhibited

better antileishmanial activity[8-10].

3.1.2. Anti-promastigotes assays on (1A-9A)

The potential of the pentavalent antimonials (1A-9A) to inhibit Leishmania growth

was evaluated using the Leishmania tropica KWH23 strain promastigotes. All

scaffolds have shown good to significant antileishmanial activity. Based on the

significant IC50 values (Table 1), the metal-scaffolds were classified in the way:

1A>3A>5A>6A>4A>2A>7A>9A>8A (Figure 6) as compared with the standard

glucantime (5.21µg/ml±1.29).Concentration-dependent anti-promastigotes test

displayed that these prepared antimonials annihilate Leishmania tropica and thus

exhibited antileishmanial activities. It is found that all the complexes are more potent

against promastigotes. Among them, complexes (1A) and (3A) exhibit excellent IC50

against promastigotes. Thesignificant activity of the complex (1A) assumes that

presence of inter- and intramolecular interactions make the carboxylate ligands more

interactive and thereby increases of the hydrophilic character of the metal complex

which also favours its absorption in the biological fluids [11].

57

Table 1.Concentration dependent activity of the synthesized antimonials against anti-

promastigotes (1A-9A) Conc

(µg/ml)

Con

trol 1A 2A 3A 4A 5A 6A 7A 8A 9A

Glucanti

me

100 100 0 0 0 0 0 0 0 0 0 0

10 100 0 33.3333 0 0 0 0 0 10 15 40

1 100 36.5853 41.6666 38.4615 38.2352 35 36.8421 38.3333 41 32 72

0.1 100 51.2195 58.3333 48.7179 52.9411 52.5 55.2631 60.6666 63.7692 61.7692 92

0.01 100 56.0975 66.6666 56.4102 64.7058 57.5 65.7894 73.3333 72.3076 68.3076 100

0.001 100 63.4146 75 69.2307 82.3529 62.5 73.6842 80 85.3846 77.3846 100

0.0001 100 87.8048 88.3333 87.1794 91.1764 87.5 89.4736 86.6666 93.6153 90.6153 100

0.00001 100 100 100 100 100 100 100 100 100 100 100

IC50 in (µg/ml)

0.1 0.48 0.077 0.26 0.23 0.4 0.58 0.67 0.38 6.4

Figure 1. Concentration dependent activity of the synthesized antimonials (1A-9A).

3.1.3. Anti-promastigotes and anti-amastigotes assays on 10A-18A (labelled in graphs

as 1-9) and their parent acids (L1-L9)

Complexes 10A-18A (labelled in graphs as 1-9 in Figure 2) and their parent acids L1-

L9 (Figure 2) were tested for their activity against the Leishmania major

58

promastigotes and human primary fibroblasts. DMSO and Amphotericin B were used

as the reference antileishmanial reagents under the same experimental conditions. The

DMSO control was set-up across the same range of concentrations as that of the

complexes and showed no adverse effects on parasites or mammalian cells even at the

highest concentrations. After 48 hours, the parent acids had little to no effect against

both the human fibroblasts and L. major promastigotes, even at the highest tested

concentrations of 100 µM. The fibroblast cells showed at most a <5% decrease in

viability, whereas the promastigotes were unaffected.

In contrast, the antimony complexes are moderately toxic, showing incomplete

promastigote elimination of 12.5% -19.8% at 100 µM. Compared to Amphotericin B

which gives complete elimination of parasites at 50 µM, and 4% at 25 µM, the

complexes did not perform as well. In general, they followed a similar trend across

the different concentrations against the promastigotes. Complex 10A (1),

incorporating 2-formylbenzoic acid, is significantly more selective as compared to the

rest of the complexes at the concentration of 50 µM, with a percentage viability of

16.7% for the promastigotes and 97.9% for the fibroblasts (Table 2).

However, this is not reflected when we look at the IC50 values for all the

complexes. Instead, Complex 11A (2), with its SI value of 2.49e33, stands out as

having the greatest selectivity amongst the complexes based on the IC50 values against

the promastigotes and fibroblasts. Previously, there were two studies by Ali et. al.,

[12] and Mushtaq et. al., [11] which had also looked at similar antimony(V) tris-aryl

dicarboxylate complexes [SbR3(O2CR)2] (R = phenyl, o-, m-, p-tolyl).

59

Figure 2. Dose response curves for complexes 10A-18A (labelled as 1-9) and their

parent acids L1-L9 for their activity against the Leishmania major promastigotes and

human primary fibroblasts.

60

Table 2. IC50 values, with standard error of the mean (SEM) from duplicate

experiments, of the complexes 10A–18A against Leishmania major promastigotes and

human fibroblasts at t = 48 h

IC50 (SEM) Selectivity Index

Sb(V)

complexes

Parent acids of

[SbPh3(O2CR)2]

R=

L. major

promastigote

Human

fibroblasts

IC50 fibroblasts/

IC50

promastigote

10A (1) (o-HCO)C6H4 11.50 (1.639) 280.2 (78.83) 24.37

11A (2) (p-CH3)C6H4COCH2CH2 14.25 (2.318) 349 (126.2) 24.49

12A (3) 2,3-(OCH3)2C6H3CH=CH 14.63 (1.768) 200.2 (58) 13.68

13A (4) 2,6-F2C6H3 9.879 (1.754) 78.11 (19.12) 7.91

14A (5) 2,5-Cl2C6H3 20.66 (2.072) 81.55 (29.37) 3.95

15A (6) (p-OC2H5)C6H4 18.88 (2.081) 206.5 (130.8) 10.94

16A (7) (m-OCOCH3) 19.26 (2.072) 74.87 (34.2) 3.89

17A (8) (p-OCH3)6H4CH=CH 14.56 (1.455) 132.3 (48.36) 9.09

18A (9) (o-OC2H5)C6H4 21.68 (2.879) 339.4 (65.8) 15.65

aNC indicates non-toxicity as graphs were non-converged

3.1.4. Anti-promastigotes and Cytotoxicity assays on (1B-8B) and (1C-20C)

Newly synthesized pentavalent antimonials (1B-8B) were assessed for their anti-

leishmaniali potency against Leishmaniai. tropica KWH23. All scaffolds presented

significant in vitro anti-leishmanial potency for varying concentration range against

Leishmania tropica KWH23. Based on significant IC50 (p < 0.01) values, the activity

profile of the compounds (1B-8B) were categorized as following:

1B>2B>3B>6B>4B>7B>8B>5B upon comparison with the standard drug glucantime

(4.4µg/ml ±0.17) (Figure 3). Concentration dependent antipromastigotes assay

displayed that studied scaffolds effectively annihilated Leishmaniatropica and

therefore showed anti-leishmanial potency.

61

Figure 3. Concentration dependent activity of the synthesized antimonials (1B-8B).

Cytotoxicity of the synthesized antimonials (1B-8B) was examined on .macrophages

extracted from human blood stream by ficoll-gastrografin method for

cytotoxicityevaluation [13, 14]. Leishmania has the capability to attack and proliferate

in the macrophages thus, these cells were used for cytotoxicity. The percentage

mortality of all the drugs was calculated. It was detected that the survival rate was

depending on the drug concentration. The results were directly associated to drug

concentrations e.g. more macrophages were viable at lower concentrations and death

percentage was higher upon increasing the dosage. The LD50values presented that the

compounds (1B-8B) were biologically active and biocompatible (Table 3).

Comparison of the IC50 of the compounds (1C-20C) against the cell culture MDA-

MB-231 and HeLa as well as against the Leishmania tropica (Table 4) has shown a

clear difference that the current compounds can be good alternative to the currently

available antimonial drugs. The antileishmanial potential of the pentavalent

antimonials (1C-20C) was evaluated using the Leishmania tropica kwh23 strain and

their cytotoxic potency against the cell culture MDA-MB-231 and HeLa. Almost all

62

scaffolds exhibited impressive antileishmanial activity and promising cytotoxicity.

Based on the significant

IC50 values of metal complexes in comparison to standard Amphotericin B

(0.36±0.04μg ml-1). The significant potency of the scaffolds can be ascribed with the

presence of lipophilic methyl groups and, also inter- and intermolecular interactions

makes the carboxylate ligands more interactive and thereby increases the absorption

of these compounds in the biological fluids.

Table 3 Antileishmanial activity (IC50) and cytotoxicity (LD50) of the synthesized

antimonials (1B-8B).

Cytotoxicity Anti-leishmanial

Compound LD50 IC50

1B 21.38 ±1.99 0.0001849 ±0.00006

2B 27.9 ±2.82 0.001346 ±0.0002

3B 12.89 ±2.2 0.00817 ±0.0003

4B 21.19 ±1.91 0.2203 ±0.00011

5B 17.8 ±2.2 1.9 ±0.00031

6B 35.9 ±3.07 0.007513 ±0.00010

7B 22.9 ±2.98 1.377 ±0.0030

8B 18.05 ±3.04 1.8 ±0.00100

Glucantime - 4.4±0.17

63

Table 4. Antileishmanial activity (IC50) against Leishmania tropica and cytotoxicity

(LD50) against MDA-MB-231andHeLaof the synthesized antimonials (1C-20C)

Codes MDA-MB-231 HeLa Leishmania tropica

IC50 ± SEM (µM)

1C 0.91 ± 0.09 1.54 ± 0.11 3.40 ± 0.15

2C 1.09 ± 0.03 18.9 ± 1.28 1.13 ± 0.04

3C 0.65 ± 0.04 3.38 ± 0.17 4.22 ± 0.07

5C 0.78 ± 0.02 0.75 ± 0.01 22.6 ± 1.12

6C 1.43 ± 0.01 8.33 ± 0.65 3.68 ± 0.09

7C 1.80 ± 0.09 4.35 ± 0.14 3.39 ± 0.04

8C 0.83 ± 0.08 11.8 ± 0.32 4.29 ± 0.02

9C 5.71 ± 0.06 4.15 ± 0.26 23.3 ± 1.09

10C 0.37 ± 0.01 0.53 ± 0.01 6.60 ± 0.26

11C 0.72 ± 0.03 0.69 ± 0.02 5.08 ± 0.03

12C 0.37 ± 0.04 4.18 ± 0.37 14.3 ± 0.18

13C 0.37 ± 0.02 0.93 ± 0.08 2.13 ± 0.07

14C 2.61 ± 0.11 3.93 ± 0.05 2.38 ± 0.02

15C 1.64 ± 0.09 5.52 ± 0.09 0.27 ± 0.05

16C 10.2 ± 0.23 5.37 ± 0.17 2.39 ± 0.06

17C 10.3 ± 0.14 5.01 ± 0.12 6.78 ± 0.04

18C 4.90 ± 0.05 0.23 ± 0.01 2.25 ± 0.10

19C 2.70 ± 0.08 3.13 ± 0.18 18.5 ± 0.33

20C 1.10 ± 0.06 7.88 ± 0.19 0.23 ± 0.05

Cisplatin 1.12 ± 0.09 17.6 ± 1.94 -

Amphotericin B - - 0.47 ± 0.09

64

3.1.5. Celltiter Blue Cell Viability Assay

The cell vialbility test was performed as reported in literature [15-18]. As a reference

the salient features of this assay have delineated below “The celltiter blue cell viability

assay (Promega, Madison, WI, USA) was employed for testing antileishmanial

potency and cytotoxicity. Tested compounds were solubilized in DMSO to make stock

solution of 20 mg/mL and diluted out in suitable culturei media. The assay was

arranged in duplicates in 96-well plates as per manufacturer’s guidlines. 106

promastigotes/mL and 105/mL J774 macrophages or primary human fibroblasts were

used. Cell viability was evaluated spectrophotometrically at 550 nm with the reference

wavelength of 630 nm [15]. The Celltiter Blue was added to samples at the time of

setting up the assay and T = 0 value was deducted from all successive readingsi as a

background value. All readings were compared to the no drug control and the percent

growth inhibition was calculated. DMSO controls were included. All plates were

assessed microscopically [16]. Under certain conditions percentage of positive control

is higher than 100% in comparison to initial percentage and this displays that there is

a growth of the species being considered. L. major V1211 was kept at 26 °C in M199

medium (Invitrogen) augmented with 10% heat inactivated fetal bovine serum (HI-

FBS). The murine macrophage J774 cell line (ATCC, Rockville, MD, USA) and

human prime fibroblast were cultivate in DMEM (Life Technologies) augmented with

10% HI-FBS at 37°C in 5% CO2. Numerous features of the Sb (V) agents have been

recommended to contribute to their potency. Carbohydrates formulate water-soluble

scaffolds with Sb and may aid to bring antimonial drug to targeted macrophages.

Comparatively nontoxic Sb(V) may be a prodrug that is converted to more lethal

Sb(III) at or around the sitei of action. Interactions of Sb with major sulfhydryl

functionality may be a key mode of action and/or toxicity. The upgrading of

procedures for assessing intracellular Sb along with an better knowledge of the

structure of sodium stibogluconate and our synthesis of chemically analogous tri- and

65

and pentavalent antimony complexes have allowed further investigations of the significance

of these hypotheses”[17, 18].

3.1.6. Cytotoxicity Assays of Compounds (1C-20C)

In vitro cytotoxicity assays of compounds (1C-20C) have been performed using SRB

cell viability test as reported in literature [13-19]. “In vitro cytotoxicity tests with cell

lines (mentioned below) were performed with the help of our collaborators (Table 5).

The ID50 values (ng/ mL) of seven reference drugs in vitro employing *SRB as cell

viability assessment is given in Table 6. The following human tumour cell lines were

used: MCFT breast cancer, EVSA-T breast cancer, WIDR colon cancer, IGROV

ovarian cancer, M19 MEL melanoma, A498 renal cancer, and H226 non-small cell lung

cancer. Cell lines WIDR, M19 MEL, 4498, IGROV and H226 belong to the currently

used anticancer screening panel of the National Cancer Institute, USA. The MCFT cell

line is estrogen receptor (ER) +/ progesterone receptor (PgR) + and the cell line EVSA-

T is (ER) -/ (PgR)”.

Table 5. Cytotoxicity (anti-cancer activity) ID50 values (ng/ml) pentavalent

antimonials (1C-20C).

Test

Compounds

Cell lines

A498 EVSA-T H226 IGROV M19 MCF-7 WIDR

1C 1543 3755 2005 2400 2045 2135 1800

2C 1200 3520 500 1005 1085 1815 2520

3C 1000 3005 400 650 460 2054 1650

4C 1705 2555 2050 3005 2030 3012 1058

5C 1805 2528 1275 2500 1200 2560 3020

6C 1525 2535 1009 1580 1200 2565 2545

66

…………………………………………………………………………………………………..Table 5 continued

8C 1525 2000 1005 1095 1210 2424 3565

9C 1015 2063 850 1006 1025 2125 2052

10C 1029 2263 1159 1327 1036 2361 2331

11C 1013 2233 788 1132 1025 2330 2157

12C 1053 2135 700 1055 1025 1459 1523

13C 1250 1980 1045 1907 2400 2132 2201

14C 950 850 1508 1695 1152 2209 2196

15C 895 1555 905 903 1033 1855 1720

16C 1265 1872 955 1163 1152 2199 2366

17C 1025 2120 850 1410 1099 2230 2205

18C 931 1902 1300 13315 1150 2202 2005

19C 950 1653 1250 1650 1050 2055 1822

20C 1051 1320 1020 1011 1500 1853 2150

Table 6. ID50 (ng/ mL) of standard compounds evaluted in vitro using SRB cell

viability test

67

REFERENCES

1. Feng, S.-S., Chien, S., Chemical Engineering Science. 2003, 58, 4087.

2. Farrell, N., “Bioorganometallics”, Jaouen, G., Ed, Wiley-VCH: Weinheim, 2005.

3. Schabel, F.M., Cancer, 1977, 40, 558-568.

4. Duffin, J., René, P., Journal of the history of medicine and allied sciences, 1991,

46, 440-456.

5. Berman, J.D., Review of Infectious Diseases, 1988, 10, 560-586.

6. Baiocco, P., Colotti, G., Franceschini, S., Ilari, A., Journal of medicinal chemistry,

2009, 52, 2603-2612.

7. Khan, H. Fatima, M.M. Taqi, M. Zia, B. Mirza, Journal of Applied Research on

Medicinal and Aromatic Plants, 2015, 2, 77-86.

8. Sadeghi-Nejad, B., Saki, J., Khademvatan, S., Nanaei, S., Journal of Medicinal

Plants Research, 2011, 5, 5912-5915.

9. Shah, N.A., Khan, M.R., Nadhman, A., BioMed research international, 2014,

2014.

10. Frézard F., Demicheli, C., Ribeiro, R.R., Molecules 2009,14, 2317-2336.


Yasinzai, M., Khan, K.M., Appl. Organometal. Chem. 2017, 31, 3606.

12. Mushtaq, R., Rauf, M.K., Bond, M., Badshah, A., Ali, M. I., Nadhman, A.,

Yasinzai, M., M.N. Tahir. Appl. Organometal. Chem. 2016, 30, 465–472.

13. Rauf, M. K., Imtiaz-ud-Din, Badshah, A., Gielen, M., Ebihara, M., de Vos, M. D.,

Ahmed, S., J. Inorg. Biochem.,2009, 103, 1135.

14. Hu, G. F. J.,Cell Biochem.,1998, 69, 326.

15. Linder, M., Hazegh-Azam, M., Am. J. Clin. Nutr.,1996, 63,797S.

16. Coates, R. J., Weiss, N. S., Daling, J. R., Rettmer, R. L., Warnick, G. R., Cancer

Res., 1989,49, 4353.

17. Hu, G.F.J., Cell Biochem, 1998, 69, 326–335.

68

18. Apelgot, S., Coppey, J., Fromentin, A., Anticancer Res. 1986, 6, 159–164.

19. Coates, R.J., Weiss, N.S., Daling, J.R., Rettmer, R.L., Warnick, G.R., Cancer

Res. 49 (1989) 4353–4356.

69

Chapter-4

RESULTS & DISCUSSION

4.1. Infrared Spectroscopy

The modern version of Infrared spectroscopy termed as FT-IR spectroscopy is a power

mean for a chemist to readily access the main/desired functionalities in the prepared

sample. This is a simple, cheaper and rapid way to analyze and entering into the next

step synthesis. This technique is very helpful in elucidating the carboxylate bearing

organo-antimony assemblies. The characteristic IR bands of organoantimony(V)

carboxylates (1A-18A) Table 1, (1B-10B) Table 2 and (1C20C) Table 3,

functionalities appeared between/near to 3470-3310(-NH2), 32653250(-NH), 3210-

2930 (C-H)aromatic., 3032-2835 (C-H)aliphatic, 1739-1619(C=O), 1587-1582 & 1331-

1228(C-N), 735-740(C-Cl), 584-545 (Sb-C), 486-441 (Sb-O). All the the absorptions

associated with (C=O) stretching frequencies appeared within the normal ranges as

reported in literature [1].

For better and clear explaination of the peak shifts here the comparison

between the spectra of a free acid i.e., 3,5-dichlorobenzoic acid and its complex with

tris(p-tolyl)antimony(V) (3B) is being carried out. The clear demarcation between C-

H and aromatic OH stretching of acids in most of the cases at 3150-2850 cm-1 is not

possible because of the overlapping of the two bands of very near frequencies as earlier

reported in the plethora of literature on synthesis and characterization aromatic

carboxylic acids and other similar type of compounds bearing the identical

functionalities. The C=O stretching at 1695 cm-1 followed by nodes at 1615 and

1565cm-1 due to the aromatic ring. Then in plane bending of O-H acid group gives

vibration at 1425 cm-1, C-O stretching vibrations at 1280 cm-1, C-C-O at 1235 cm-1,

O-C-O at 1097 cm-1 and the O-H bending out of plane of acid at 907 cm-1 and the out

of plane aromatic CH band at 768 cm-1. The infrared spectrum of the complex (3B) of

the above described acid with organoantimony(V) is given chapter-2 and also in Table

70

2 of this chapter. “The attention is focused to the symmetric and asymmetric carbonyl

bands near 1657cm-1 and 1300 cm-1, respectively. The shift from 1694cm-1(C=O) to

1652 cm-1 is attributing to converting the COO into the carboxylates with

rearrangement of bonds into one and half linkage. The appearance of new band in the

lower infra-red region (584-545cm-1) and 486-441cm-1 are for SbC deformations and

Sb-O stretching which are not present in the case of free ligands and on agreement

with literature”[2-9].

71

Table 1.Characteristic FTIRabsorptions (cm-1) for complexes (1A-18A)

Complexes C-Haromatic C-Haliphatic C=O C-O Sb-C Sb-O Miscellaneous

1A 3094 1663 1253 562 463 3455-3345

(-NH2)

2A 3054 2920 1619 1265 550 457

3A 3026 1629 1260 564 448 3265(-NH)

4A 3068 1647 1258 583 444 739(C-Cl)

5A 3057 2978, 2937 1647 1278 555 458

6A 3054 1654 1269 562 447 1587(CN)

7A 3018 2926 1657 1259 582 484

8A 2936 2840 1652 1265 548 448

9A 3048 2928 1641 1262 563 452 737(C-Cl)

10A 3096, 3079 2992, 2972 1671,

1674

1294 561 448

11A 3028 2968, 2844 1668 1255 564 451

12A 3021 2983, 2944,

2888

1699 1267 569 448

13A 3120, 2930 1630 1288 570 447

14A 3092, 3082 1675 1295 583 444

15A 3264, 3080 2941, 2902 1738 1298 578 458

16A 2930 2891, 2836 1685 1290 581 455

17A 3057 2902, 2844 1664 1265 571 450

18A 3261, 3078 2980, 2942 1739 1294 569 456

Range obs.

(cm-1)

3261-2930 2992-2836 1739-

1619

1298-

1253

583-

550

463-

444

-

72

Table 2.Characteristic FTIRabsorptions (cm-1) for complexes (1B-10B)


1B 3023 2920 1632 1327 551 481

2B 3210 2921 1635 1256 562 484 3250(-NH)

3B 3070 2910 1638 1319 579 485 740(C-Cl)

4B 3024 2937 1647 1244 571 485

5B 3035, 3025 2919 1638 1331 557 484 1583 (C-N)

6B 3100, 3082 3020, 2939 1646 1258 564 475 3444,3334

(-NH2)

7B 3010 2916 1652 1239 584 480

8B 2930 2835 1640 1243 545 486

9B 3048 2928 1635 1258 562 477

10B 3046 2926 1634 1248 565 476

Range obs.

(cm-1)

3210-2930 3020-2835 1653-

1632

1331-

1243

584-

545

486-

476

-

73

Table 3.Characteristic FTIRabsorptions (cm-1) for complexes (1C-20C)


1C 3143 2923,

2860

1661 1316 563 440

2C 3228 2929 1651 1263 550 445

3C 3048 2924 1645 1300 600 442

4C 3042 2934,

2910

1653 1239 555 458

5C 3030 2921 1665 1313 561 438

6C 3029 2926 1637 1255 556 435

7C 3010 2922 1631 1256 561 435

8C 3029 2921 1654 1266 557 439

9C 3028 2922 1650 1328 568 433

10C 3137 2922 1645 1266 563 439

11C 3025 2923 1639 1308 532 441 718 (C-S)

12C 3027 2922 1647 1255 567 441 1610 (-

CH=CH-)

13C 3012 2923 1638 1321 561 451

14C 3015 2911 1640 1268 563 439 1582 (C-N)

15C 3019 2919 1637 1236 561 458 3410 (O-H)

16C 3022 2920 1639 1240 568 440 3368, 3310

(-NH2)

17C 3047 2918 1639 1306 565 457 3232 (-NH)

18C 3029 2921 1631 1234 561 441 3286(-NH)

19C 3028 2919 1651 1328 571 437 1579 (-CN)

20C 3026 2921 1646 1260 575 451 766 (C-S)

Range obs.

(cm-1)

3228-

3010

2934-

2860

1665-

1631

1328-

1228

584-

545

486-

441

-

74

4.2. Multi-nuclear (1H, 13C) NMR Spectroscopy

The magnetically distinct hydrogen and carbon atoms of a molecule can be distinguish

by their chemical shift values (δ), referring to molecular symmetry and the expected

impacts of neighboring electronegative atoms and unsaturated groups. It is necessary

to understand the general pattern of chemical shifts (δ) for the elucidation of NMR

spectra. The chemical shift values of 1H and 13C signals are influenced by the vicinity

of electronegative atoms (O, N, F, Cl, etc.) in the bonding linkage and by the vicinity

to π-bonded groups (C=C, C=O, aromatic) directly through space. Electronegative

atoms drift the resonances frequency to the left (higher chemical shift, downfield

shift), whereas unsaturation shift to the left (higher chemical shift, downfield) when

the pretentious nucleus is in the plane of the unsaturated group, but have the reverse

effect (lower chemical shift to the right or “upfield”) in the region of above and below

this plane [10].

The 1H NMR data for the synthesized organoantimony(V) complexes

(1A18A), (1B-10B) & (1C-20C) delineated in chapter-2, shows that the 1H NMR

spctra for the organoantimony(V) scaffolds depict the presence of aromatic protons at

7.23-8.59 ppm as earlier given in literature[9, 10]. The other resonances around 2.37-

2.40, 3.40-3.35 and 3.85-3.80 ppm are assigned to –CH3, –CH2-, –OCH3 groups

respectively. The –NH2 and –NH– protons of the ligands around 5.60 and 9.55 ppm,

respectively. 1H NMR spectra of the free ligands reveal that the singles resonating at

10.85 ppm are due to the –COOH group [7, 9]. “The 13C-NMR spectra depict all the

signals owing to the chemically distinct carbon atoms existent in these complexes. The

chemical shift values of aromatic carbon of the synthesized pentavalent antimonials

are designated on the reference of signal intensities and then equating with the

literature. The 13C NMR data of all compounds display a notable downfield shift of

all carbons resonant frequencies with comparison to the free ligand since an electronic

cloud relocate from the ligand to the metal. The 13C signal for -CH3 ariesd at 9.5–22.5

75

ppm. The 13C signals attributing to aryl group appeared at 110.0– 160.0 ppm and the

signals for carbonyl carbon gave signal at 167.0–180.0 ppm” [7, 11].

4.3. Single Crystal XRD Analysis

The synthesized organoantimony(V) complexes have been crystallized in suitable

solvent and selected for the single crystal X-ray diffraction analysis.

4.3.1. Bis(2-aminobenzoato)(triphenyl)antimony(V) (1A) and Bis(3,5dichlorobenzoato)

(triphenyl)antimony (V) (4A)

The antimony(V) complexes in (1A) and (4A) are five-coordinate with geometries in

between the trigonal bipyramidal. and square pyramidal. In the trigonal bipyramidal

consideration, the monodentate carboxylate ligands occupy axial position with a syn

conformation and the phenyl moieties rest at equatorial position, while in the square

pyramidal extreme the C7-C12 (for 1A) or C13a-C18a (for 4A) phenyl group is apical.

A molecular arrangement of the complex in (1A) is presented in Figure 1 and of the

complex in (4A) in Figure 2.

The geometries in these complexes closely conform to the typical geometry

found for complexes with essentially synmonodentate carboxylate ligands in

approximately 53 similar compounds listed in the Cambridge Structural Database

(four additional compounds listed in the database are with carboxylate ligands serving

as bidentate and monodentate as well). The 2-aminobenzoato- (1A) and

3,5dichlorobenzoato- (4A) ligands show average C-O bond length of 1.271(3) and

1.261(3) Å, respectively. The Sb-O bond lengths for these complexes cluster

atcomparatively longer values 2.1286(18) and 2.1134(15)Å. The non-ligating Sb…O

contacts, involving O atoms is in the range of 2.726-3.010 Å, a contact range that has

beenmost frequently found for similar complexes [12, 16]. Particulars of the data

collection and structure refinement parameters are summarized in Table 4.

76

Figure 1.Molecular structure of (1A) with labels for the core atoms only. H-atoms

are drawn as circles of arbitrary radii.

Figure 2.Molecular structure of (4A) with labels for the core atoms only. H-atoms

are drawn as circles of arbitrary radii.

77

78

The benzoato- ligands are almost coplanar in all two complexes (angle between mean

plane normals of 10.50(5) and 3.77(5)º for (1A) and (4A)respectively. O-SbC(7) (for

1A) or O-Sb-C(13a) (for 4A) angles <90 between the apical phenyl and basal

carboxylate ligands indicate that the carboxylate ligands are distorted above the basal

plane. Similar distortions are found for the related complexes in the CSD. Sb-C bond

lengths average 2.122(3) and 2.134(3) Å for structures (1A) and (4A), respectively.

The average Sb-C bond lengths for these two structures fall within the range 2.089-

2.130 Å, most frequently observed for similar complexes [15]. Selected geometrical

parameters are listed in Table 5.

79

Table 6.The intermolecular and intramolecular hydrogen bonds for compound

The crystal packing in (1A) (orthorhombic Pccn) compared to (4A) (triclinic P ̅) bears

more complicated unit cell packing in which double layers of Sb(V) complexes are

stacked along c(Figure 3).

Figure 3: Unit cell packing for (1A) in which double layers of Sb(V) complexes are

stacked along c.

80

Figure 4. Supramolecular structure of complex (1A) showing 3D network of short

contacts and H-bonds are stabilizing crystal structure.

In the crystal structure (1A), molecules are connected through C-H…N and N-H…O

intermolecular and N-H…O and C-H…O intramolecular interactions forming a 3D

network extended throughout the crystal system (Figure 4) Table 6. The molecular

structures with greater multitude of interactions are considered to be very potent

regarding biological activities as evident from (1A) and (4A) (Figure 4). The crystal

structure of (4A) is stabilized via C-H…Cl and Cl…Cl interactions along c-axis forming

a type motifs (Figure 5) [15].

Figure 5.One-dimensionalview of molecules (4A) along c-axis forming a

type motifs stabilized by alternate Cl…Cl and C-H…Cl short contacts.

81

4.3.2. Crystal Structures of Compounds (10A), (11A), (13A), (14A) and (17A).CHCl3

The molecular structures of compounds (10A), (11A), (13A), (14A) and (17A).

CHCl3 were determined by single crystal X-ray diffraction methods (Figure 6).

82

Figure 6. Molecular diagrams of SbPh3L2: (10A), (11A), (13A), (14A)

and(17A).CHCl3. Solvate (CHCl3) part in 17A have been omitted.

Details of the data collection and structure refinement parameters are summarized in

Table 7(a & b). Each complex is monomeric and the coordination geometry of the

83

Sb(V) center is approximately trigonal bi-pyramidal with the three phenyl rings

equatorial and an oxygen atom of the two carboxylate ligands in the axial positions.

The coordination geometries of (10A), (11A), (14A) and (17A).CHCl3 are distorted

from a regular polyhedron as indicated by the significant deviations of the C-Sb-C

angles from 120° (Table 8) with notably one larger angle of 143.75(7) (10A), 154.9(1)

(11A), 152.1(1) (14A) and 137.61(8) (17A.CHCl3) Å. In each of these complexes, the

axial carboxylate groups are approximately coplanar (C-O-O-C torsion angles 3.3-

21.9°) with the second oxygen atom of each group bisecting the larger C-Sb-C angle.

The exception is compound 13A in which the axial carboxylate groups are twisted

relative to each other (C-O-O-C torsion angle 116.0°) and the second oxygen atom of

each carboxylate group bisects opposing C-Sb-C angles, resulting in a more regular

trigonal geometry (Table 8). In all complexes, the Sb-C distances fall in a narrow

range (2.096(1)-2.118(1) Å) whereas there are some differences in the Sb-O distances

2.1035(9)-2.157(2) Å, with longer values observed for complexes 11A and 14A and

which are associated with corresponding closer non-bonded Sb...O distances (2.63-

2.69 Å, cf 2.96-3.14 Å for 10A, 13A and 17A) to the second of the carboxylate oxygen

atoms.

84

85

86

Table 7-b

87

4.3.3. Crystal Structures of Bis(4-methylbenzoato)tris(p-tolyl)antimony(V) (1B), Bis(3,5-

dichlorobenzoato)tris(p-tolyl)antimony(V) (3B) and

Bis(nicotinato)tris(ptolyl)antimony(V)(5B)

The structures of 1B, 3B and 5B are depicted in Figs.7-9, respectively and data

collection and refinement parameters are delineated in Table 9. Selected bond lengths

and bond angles appear in Table 10. The complex shows two ligand molecules

covalently bond through the oxygen atom with antimony atom, and three p-tolyl

groups originating three Sb–C bonds.

The antimony(V) complexes 1B, 3B, and 5B are five-coordinated with

geometries intermediate between trigonal bipyramidal and square pyramidal. In the

trigonal bipyramidal extreme, the monodentate carboxylate ligands are axial with a

syn conformation and the tolyl ligands occupy equatorial position, while in the square

pyramidal extreme the C4X (for 1B and 5B) or C1-C7 (for 3B) tolyl ligand is apical.

The thermal ellipsoid plots of the complexes 1B, 3B and 5B are presented in Figures

7, 8 & 9 respectively.

Figure 7. ORTEP plot (50% ellipsoids) for the coordination complex in 1B with labels

for the core atoms only. H-atoms are drawn as circles of arbitrary radii.

88

Figure 8. ORTEP plot (50% ellipsoids) for the coordination complex in 3B with labels

for the core atoms only. H-atoms are drawn as circles of arbitrary radii.

Figure 9.ORTEP plot (50% ellipsoids) for the coordination complex in 5B with labels

for the core and N-atoms only.

The geometries in these complexes closely conform to the typical geometry found for

complexes with essentially syn monodentate carboxylate ligands in 50 similar

89

compounds listed in the Cambridge Structural Database (four additional compounds

listed in the database with bidentate carboxylate ligands are, arguably, monodentate

as well). In contrast, complexes with a pronounced twist of the carboxylate groups

toward an anti-arrangement exhibit five-coordinate geometries far closer to trigonal

bipyramidal, as shown by C-Sb-C angle values clustered about 120º. So, for example,

the 4-methylbenzoato- (1B), 3,5-dichlorobenzoato- (3B), or nictinato- (5B) ligands

show average C-O bond lengths of 2.1251(12), 2.1257(120, and 2.1176(13) Å,

respectively, while Sb-O bond lengths for similar complexes cluster most frequently

in a slightly longer length range 2.122 to 2.137 Å. The Sb…O contacts involving non-

ligating O atoms are in the range of 2.8-3.0 Å, a range that corresponds to the most

frequently found contact distance for similar complexes. Details of the crystal data,

data collection, structure determination conditions and parameters are summarized in

Table 9. The benzoato- or nicotinato- ligands are almost coplanar in all three

complexes (angle between mean plane normals are of 5.10(6) and 4.45(5)º for 1B and

5B respectively) with ring N-atoms anti in 5B. The O-Sb-C(41) (for 1B and 5B) or

O-Sb-C(1) (for 3B) angles <90 between the basal carboxylate and apical tolyl ligands

indicate that the carboxylate ligands are distorted above the basal plane (Table 10).

Similar distortions are found for all but one of the related complexes in the CSD. The

Sb-C bond lengths average are 2.107(1), 2.110(2), and 2.113(2) Å for structures 1B,

3B, and 5B, respectively, with the apical C4X ligand in structure 5B showing small,

but significant, elongation relative to the basal C3X and C5X ligands (Average Sb-C

bond lengths for these three structures fall within the range 2.105-2.115 Å most

frequently found for similar complexes.). Among metrical parameters, the C31-Sb1-

C51 angle exhibits the strongest distortion from a trigonal bipyramidal geometry

(143.32(9)º for 1B, 145.92(11)º for 3B,and 145.84(11)º for 5B). The apical C4X

ligand is twisted relative to the basal C1X and C2X ligands in 1B (14.75(5) and

15.19(5)º, respectively between mean plane normals), while almost coplanar with the

same ligands in 5B (5.90(9) and 4.51(7) º respectively) and in 3B. The trans C3X and

C5X tolyl groups exhibit a slight twist about the Sb-C axis in structure 1B, and the

90

C3X group is slightly bent toward the O11 ligand in 5B, so that these groups are not

coplanar (angles between mean plane normals are 10.71(8)º for 1B and 11.17(2)º for

5B), although they are essentially coplanar in 3B [14].The selected geometrical

parameters are presented in Table 10 .

91

92

93

The disparate crystal packing in 1B (orthorhombic Pbca) compared to 3B and 5B

(triclinic P ̅) bears comment. The structure of 1B displays a more complicated unit cell

packing in which double layers of Sb(V) complexes are stacked along c-axis. The

double layers are composed, in turn, of distorted orthohexagonal packed (b/a=

1.87410(2) compared to the ideal ratio of 1.73205) layers of complexes in which

phenyl ring 4 projects along positive (or negative for the neighboring layer) c-axis to

nest into a cavity formed by the other four phenyl rings of the neighboring layer, The

cavity walls are formed by vertical phenyl rings arranged in a square with the plane of

projecting phenyl ring 4 approximately parallel to the planes of phenyl rings numbers

3 and 5, and approximately perpendicular to the planes of phenyl rings 1 and 2 (of the

carboxylate ligands). Within the double layers there are voids formed between the

projecting phenyl rings (53 Å3 with a probe radius of 1.2 Å and a grid spacing of 0.2

Å), shown in the packing diagram of Figure 10, that are large enough to accommodate

a water molecule but too small for other common solvents.

Figure 10. Packing diagram for 1B with atoms plotted as spheres of arbitrary radii

and with axis labels (a horizontal and c vertical). The voids between projecting phenyl

rings of the double layers are depicted.

However, water was scrupulously avoided in preparation of the compound, no

significant residual electron density is observed in the voids, and application of the

94

SQUEEZE algorithm to the structure leads to deterioration of every measure of

structure refinement quality-hence we conclude that the voids are empty.

Unit cell parameters for 5B are consistent with distorted hcp layers of complexes in

the ab-plane stacked along c with phenyl ring 4 projecting above (or below for the

neighboring) layer. However, the complexes are rotated out of the layer to produce

ribbons two complexes wide directed along a with ribbons aggregated in (012) lattice

plane as the more prominent packing feature. Here complexes on opposite sides of

the ribbon have phenyl ring 4 projected in opposite directions away from the ribbon

plane. Rotation of the complexes out of the layer provides a more efficient packing

than 1B, with a calculated density almost 0.1 g/cm3 higher than 1B at ambient

temperature and no calculated voids found under the same conditions as stated above.

A packing diagram for 5B viewed down the ribbon axis is presented in Figure 11.

Figure 11. Packing diagram for 5B, viewed parallel to a, with atoms drawn as spheres

of arbitrary radii and with unit cell axis labels. The layers of ribbons in (012) are

viewed end-on.

The packing in 3B is distinctly different: chains of complexes parallel to [101]

(formed by face-to face overlap of carboxylate- ligand aromatic rings) assemble into

layers coincident with (1 ̅1), as shown in Figure 12. Phenyl rings of the apical tolyl

95

complexes project outward both above, and below the layer, to nest into voids formed

between chains of complexes in the neighboring layers. These voids are readily

apparent as the empty spaces visible in the layer packing diagram in Figure 12.

Figure 12. View of the layer packing in 3 viewed perpendicular to the (1 ̅1) plane with

[101], the direction of the chains of complexes formed by face-to-face overlap of

benzoate- phenyl rings, horizontal. The position of one of the voids, as discussed in

the text, is marked with an X.

Less apparent are the small voids offset from a large void, one such small void is

marked with an X in Figure 12, that each remain as an unfilled void with a volume of

23 Å3. Thus the three structures exhibit a range of packing behavior with, in the case

of 1B and 3B, the presence of voids that could indicate the possibility of

polymorphism or favorable conditions for co-crystal formation [16].

96

REFERENCES

1. Fregona, D., Giovagnini, L., Ronconi, L., Marzano, C., Treeevisan, A., Sitran, S.,

Bordin, B., J. Inorg. Biochem., 2003, 93, 181.

2. Nakamoto, K., Infrared and Raman Spectra of Inorganic and Coordination

Compounds, 4th (ed.), Wiley, New York, 1986.

3. Wiles, D. M., Gingkas, B. A., Suprlnchuk, T. Canadian Journal of

Chemistry,1967, 45, 469.

4. Palacios, E. G., Juaraez-Lopez, G., Monhemius, A. J., Hydrometallurgy, 2004,

72, 139.

5. Ibrahim, M., Nada, A., & Kamal, D. E., Indian journals of Pure & Applied Phys,

2005, 43, 911.

6. Henry, F. H. Jr., James P. C., J. Am. Chem. Soc., 1957, 79 (13), 3318.

7. Wen, L., Yin, H., Li, W., Wang, D. Inorg. Chim. Acta, 2010, 363(4), 676.

8. Cesaro, S. N., Vibrational Spectroscopy, 1998, 16, 55.

9. Rauf, M. K., Saeed, M. A., Imtiaz-ud-Din, Bolte, M., Badshah, A., Mirza, B., J.

Organomet. Chem.,2008, 693, 3043.

10. Jacobsen, N. E., NMR Spectroscopy Explained Simplified Theory, Applications

and Examples for Organic Chemistry and Structural Biology. John Wiley & Sons,

Inc., Hoboken, New Jersey, 2007.

11. Kolinowski, H. O., Berger, S., Brown, S., 13C NMR Spectroscopy, ThiemeVerlag,

Stuttgart, Germany, 1984.


Kedzierski, L. and Andrews, P.C., Dalton Trans.2013, 42, 16733-16741.

13. Gibbons, N., Sowerby, D. B., J. Organomet. Chem.,1998, 555, 271.

14. Liu, R.C., Ma, Y. Q., Yu, L., Li, J. S., Cui, J.R., Wang, R.Q. Appl. Organomet.

Chem.,2003, 17, 662.

15. Mushtaq, R., Rauf, M.K., Bond, M., Badshah, A., M. I. Ali, Nadhman, A.,

Yasinzai, M., Tahir, M.N.Appl. Organometal. Chem. 30 (2016) 465–472.

97


Yasinzai, M., Khan, K.M., Appl. Organometal. Chem. 31 (2017) 3606.


Kedzierski, L., Andrews, P.C. Dalton Trans. 2013, 42, 16733-16741.

21. Almeida M.C., Silva, A.C., Barral, A., Barral, M.N., Mem. Inst. Oswaldo Cruz.

2001,95, 221-223.

22. Nadhman, A., Nazir, S., Khan, M.I., Arooj, S., Bakhtiar, M., Shahnaz, G.,Yasinzai

M., Free Radical Biol. Med.2014,77, 230.

23. Mikus, J., Steverding, D., “A simple colorimetric method to screen drug

cytotoxicity against Leishmania by using the dye Alamar Blue.” Parasitol.

Int.2000, 48, 265-269.

24. Kedzierski, L., Curtis, J. M., Kaminska, M., Jodynis-Liebert, J., Murias, M., “In

vitro antileishmanial activity of resveratrol and its hydroxylated analogues against

Leishmania major promastigotes and amastigotes.” Parasitol. Res.,2007, 102, 91-

97.

25. Roberts, W. L., Rainey, P. M., “Antimony quantification in Leishmania by

electrothermal atomic absorption spectroscopy.” Anal. Biochem. 1993, 211, 1–6.

26. Roberts, W. L. and Rainey, P. M.,“Antileishmanial activity of sodium

stibogluconate fractions.”Antimicrob. Agents Chemother., 1993,37, 1842–1846.

27. Keepers, Y. P., Pizao, P. E., Peters, G. J., van Ark-Otte, J., Winograd, B., Pinedo,

H. M., “Comparison of the sulforhodamine B protein and tetrazolium (MTT) assays

for in vitro chemosensitivity testing.” Eur. J. Cancer, 1991, 27, 897.

28. Sharma, P., Perez, D., Cabrera, A., Rosas, N., Arias, J. L., “Perspectives of

antimony compounds in oncology.” Acta .Pharmacol. Sin., 2

29. Rauf, M. K., Imtiaz-ud-Din, Badshah, A., Gielen, M., Ebihara, M., de Vos, M. D.,

Ahmed, S., J. Inorg. Biochem.,2009, 103, 1135.

30. Hu, G. F. J.,Cell Biochem.,1998, 69, 326.

31. Linder, M., Hazegh-Azam, M., Am. J. Clin. Nutr.,1996, 63,797S.

98

32. Coates, R. J., Weiss, N. S., Daling, J. R., Rettmer, R. L., Warnick, G. R., Cancer

Res., 1989,49, 4353.

LIST OF PUBLICATIONS

1. R. Mushtaq, M. Khawar Rauf, M.Bolte, A. Nadhman, A.Badshah, M. N. Tahir,

M. Yasinzai, K. M. Khan. (2017) Synthesis, characterization and antileishmanial

studies of some bioactive heteroleptic pentavalent antimonials. Appl.

Organometal. Chem. 31, 3606-3613.

2. R. Mushtaq, M. Khawar Rauf, M. Bond, A.Badshah, M. I. Ali, A. Nadhman, M.

Yasinzai and M. N. Tahir. (2016) A structural investigation of heteroleptic

pentavalent antimonials and their leishmanicidal activity. Applied Organometallic

Chemistry. 30 (2016) 465–472.

3. M. Khawar Rauf, R. Mushtaq, A. Badshah, R. Kingsford-Adaboh, J. J. E. K.

Harrison and H.Ishida. (2013) Synthesis and Crystal Structure Studies of Three N-

Phenylphthalimide Derivatives. Journal of Chemical Crystallography, 43:144–150

Rabia Mushtaq - Pakistan Research Repository

Documents