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.

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: bhoomireddyramadevi@gmail.com.

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: pramoddubey7@gmail.com

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:bhoomireddyramadevi@gmail.commailto:pramoddubey7@gmail.com

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

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.

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 .

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:

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:

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