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Project Proposal – 1
Synthesis of Novel Heterocyclic Cinnamic Benzimidazole and
Quinolone Scaffolds as potential anti-tuberculosis agents
submitted to the
CSIR, New Delhi
(Open Source Drug Discovery)
under the
OSDD Chemistry Outreach Program
by
Dr. B. Rama Devi
Department of Chemistry,
Jawaharlal Nehru Technological University Hyderabad College
of
Engineering,
Kukatpally, Hyderabad (A.P.)-500 085.
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1. Name and Complete Address of the Investigator:
Dr. B. Rama Devi,
D/O: Rama Chandra Reddy,
Associate Professor in Chemistry,
Dept. of Chemistry,
Jawaharlal Nehru Technological University Hyderabad College of
Engineering,
Kukatpally, Hyderabad (A.P.) – 500085.
Email: [email protected].
Name of Co-Investigator:
Dr. P. K. Dubey,
Professor & Chairman BOS in Chemistry,
Dept. of Chemistry,
Jawaharlal Nehru Technological University Hyderabad College of
Engineering,
Kukatpally, Hyderabad (A.P.) – 500085.
Email: [email protected]
2. Title of the Project:
Synthesis of Novel Heterocyclic Cinnamic Benzimidazole and
Quinolone Hybrid Scaffolds as
Potential Anti-tuberculosis agents.
3. Preamble:
Tuberculosis (TB) is a threat to worldwide public health, mainly
caused by Mycobacterium
tuberculosis (M.tb.) bacteria species. This contagious disease
is transmitted through air and most
commonly affects the lungs, which is responsible for more than
75 percent of cases1. According
to statistics, one-third of the world’s population is currently
infected with the TB bacillus totaling
million people worldwide develop active TB and almost 3 million
die2. The high susceptibility of
human immunodeficiency virus-infected persons to the disease3,
the emergence of multi-drug-
resistant (MDR-TB) strains4,5,6
and extensively drug-resistant (XDR-TB) ones have brought
this
infectious disease into the focus of urgent scientific interest.
For this reason, there is a growing
need and urgency to discover new classes of chemical compounds
acting with different
mechanisms from those currently used. Cinnamic acid and
derivatives have a century-old history
mailto:[email protected]:[email protected]
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as antituberculosis agents. For example, gradual improvement was
observed when the TB-
patients were treated with cinnamic acid (1) prepared from
storax7. Furthermore, in 1920s,
ethylcinnamate8 (2), sodium cinnamate
9 (3) and benzylcinnamate
10 (4) were reported to be
efficacious in the treatment of TB (Fig. 1). Nevertheless, we
feel that this class of molecules
remained underutilized until recent years. Particularly in the
last two decades, there has been
huge attention towards various natural and unnatural cinnamic
derivatives and their
antituberculosis efficacy. In recent years, transcinnamic acid
derivatives have also attracted
much attention due to their antioxidative11
, antitumor12
and antimicrobial13, 14
properties.
O
OH
O
ONa
O
O
O
O
(1) (2) (3) (4)
Fig 1.
Benzimidazole scaffold being an important pharmacophore and
privileged structure in
medicinal chemistry15,16
, a new series of 5-(nitro/bromo)-styryl-2-benzimidazoles (6)
was
synthesized17
by simple condensation of 5-(nitro/bromo)-O-phenylenediamine (5)
with trans-
cinnamic acids in ethylene glycol for 6 h at around 200°C (Fig.
2) . The in vitro anti-TB
activities of compounds and on the M.tb. H37Rv were determined
at 7.25 μg/mL concentration.
Interestingly, the bromo-substituted benzimidazole derivatives
exhibited the best results with 63-
83% inhibition.
NH2
NH2R
HO
O
R1 N
HN
CH
HC
RR1
Ethyleneglycol
R = Br, NO2 R1 = H, 3,4-di-OCH3,
4-CH3,2,4-di-Cl,
3-OH
(5) (1) (6)
Fig 2.
In addition to Cinnamic acid derivatives, new Flouro Quinolone
derivatives are being used to
treat tuberculosis like Levofloxacin, Moxifloxacin and
Gatifloxacin which were considered
potent bactericidal and sterilizing agents18
currently used for Drug resistant tuberculosis.
Tuberculosis (TB) remains one of the main causes of morbidity
worldwide, and the
emergence of multi-drug resistant (MDR) Mycobacterium
tuberculosis strains in some parts of
the world has become a major concern. The decrease in activity
of the major anti-TB drugs, such
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as isoniazid and rifampicin, is an important threat and
alternative therapies are urgently required.
The anti-TB activity of the fluoroquinolones 19
has been under investigation since the 1980s.
Many are active in vitro but only a few, including ofloxacin,
ciprofloxacin, sparfloxacin,
levofloxacin and lomefloxacin, have been clinically tested.
Fluoroquinolones can be used in co-
therapy with the available anti-TB drugs20
. However, the choice of fluoroquinolone should be
based not only on the in vitro activity, but also on the
long-term tolerance. Fluoroquinolones are
novel anti-TB drugs to be used when a patient is infected with a
MDR-TB strain.
Quinolones possess many desirable attributes for a first-line
therapeutic agent against
TB21
. These include potent bactericidal activity against both
replicating and non-replicating
Mycobacterium tuberculosis (M.tb), favorable long-term safety
indicators, oral bioavailability,
and an ability to penetrate macrophages. Moxifloxacin, a proven
and effective antibacterial agent
developed by BayerHealthcare AG, is a third generation quinolone
compound, and has
demonstrated effective sterilizing activities against M.tb.
However, the quinolone class has not
been extensively optimized for a TB indication.
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The QSAR studies of above compounds revealed that the respective
positions of Quinolones and
Styryl derivatives are responsible for their bactericidal
activity.
N
HNX
R N
O O
OHF
N(R)
HN (S) R
X
H
N
N
N
O
OH
O
X H
Quinolone-benzimidazole hybrid molecules
Essential for DNA gyrase binding
Essential for enzyme binding
Controles Potency
Controls Pharmakokinetics
Controls Potency,Spectrum andPharmakokinetics
Controls Gyrase andBacterial Potency
Controls Potency andGram +ve Activity
Essential forEnzyme inhibition
Essential for Bactericidal activity
N
N
HC
O
H
OH
O
CH
F
NR
OR
F
R1
R
The objective of the quinolone-benzimidazole scaffold project is
to develop a new
generation of DNA gyrase inhibitors that will be effective in
shortening TB therapy, while
maintaining an excellent safety and tolerability profile. The
new agents should also be suitable
for the treatment of multidrug-resistant (MDR) TB and TB/HIV
co-infections without
prohibitive drug-drug interactions with antiretroviral drugs
(ARVs) used to treat HIV/AIDS.
OBJECTIVES:
Synthesis of libraries of
5-Cyclopropyl-2-[2-(4-fluoro-phenyl)-vinyl]-8-oxo-5,8-
dihydro-3H-imidazo[4,5-g]quinoline-7-carboxylic acid &
8-Fluoro-2-[2-(4-fluoro-
phenyl)-vinyl]-6-oxo-9-piperazin-1-yl-6H-imidazo[4,5,1-ij]quinoline-5-carboxylic
acid derivatives using in-house developed methodology .
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Evaluation of the structures by In Silico studies using computer
simulated molecular
modeling, docking studies to predict toxicity and ADME
parameters.
Evaluation of the compounds for their anti-tuberculosis activity
and development of the
structures using SAR studies.
Design, synthesis and evaluation of novel focused libraries of
5-Cyclopropyl-2-[2-(4-
fluoro-phenyl)-vinyl]-8-oxo-5,8-dihydro-3H-imidazo[4,5-g]quinoline-7-carboxylic
acids &
8-Fluoro-2-[2-(4-fluoro-phenyl)-vinyl]-6-oxo-9-piperazin-1-yl-6H-
imidazo[4,5,1-ij]quinoline-5-carboxylic acids based on SAR
against Tuberculosis.
WORK PLAN & SCHEMATIC REPRESENTATION:
Scheme 1:
N
N
NR
O
OH
O
F H
O2N
N
HN
CH3
OHC O2N
N
HN H
C CH
F
F
O2N
NH2
NH2
H3C OH
O
4 N HCl
HO
O
F
Ethylene glycol
O2N
N
RN H
C CH
FH2N
N
RN H
C CH
(E)F Na2S
DMS,K2CO3,
DMF
Scheme 1:
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F
Cl
NH2
NH2
CH3COOH
4 N HCl
F
Cl N
HN
CH3EMME
F
Cl N
NCH3
COOEt
EtOOC
Ph-O-Ph F
Cl N
NCH3
H
COOEt
O
(1)(2)
(3) (4)
F
Cl N
NCH3
H
COOEt
O
(4)
Ar
O
HF
Cl N
N HC
H
COOEt
O
(5)
CH
Ar
R-NH
F
N N
NCH3
H
COOH
O
(6)R
R1
R1
F
N N
N HC
H
COOH
O
RR1
(7)
R-NH
R1
CH
ArAr
O
H
Scheme 2:
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TIME LINE:
One Year (Aug-2012 to July-2013)
S.No. Time Duration Work to be done
1. 2 months
Literature Survey
2. 1 month
Purchasing of required chemicals, equipment
etc.
3. 6 months Synthesis of target molecules
4.
3 months Structural characterization and submission for
anti-tuberculosis analysis.
BUDGET:
S. No. ITEM BUDGET (Rs.)
(for 12 months)
RUPEES
A. Recurring
Salary-(project
fellow/assistant-1@16000/-
month
1,92,000=00 1,92,000=00
Consumables (Chemicals and
glassware)
2,00,000=00 2,00,000=00
Contingency 50,000=00 50,000=00
B. Equipment 5,00,000=00 5,00,000=00
C. Grand Total (A+B) Amount 9,42,000=00
(Rupees Nine lakh forty two thousands only)
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http://www.ncbi.nlm.nih.gov/pubmed?term=Bryskier%20A%5BAuthor%5D&cauthor=true&cauthor_uid=11829714http://www.ncbi.nlm.nih.gov/pubmed?term=Lowther%20J%5BAuthor%5D&cauthor=true&cauthor_uid=11829714http://www.ncbi.nlm.nih.gov/pubmed/11829714?dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/11829714?dopt=Abstract