Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose 2'-oxidase.

Landge S; Mullick AB; Nagalapur K; Neres J; Subbulakshmi V; Murugan K; Ghosh A; Sadler C; Fellows MD; Humnabadkar V; Mahadevaswamy J; Vachaspati P; Sharma S; Kaur P; Mallya M; Rudrapatna S; Awasthy D; Sambandamurthy VK; Pojer F; Cole ST; Balganesh TS; Ugarkar BG; Balasubramanian V; Bandodkar BS; Panda M; Ramachandran V

doi:10.1016/j.bmc.2015.11.017

Back

Journal article

Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose 2'-oxidase.

Landge S iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Mullick AB iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Nagalapur K iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Neres J École Polytechnique Fédérale de Lausanne, Global Health Institute, Switzerland.
Subbulakshmi V iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Murugan K iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Ghosh A iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Sadler C Global Safety Assessment, AstraZeneca, Alderley Park, Mereside, UK.
Fellows MD Global Safety Assessment, AstraZeneca, Alderley Park, Mereside, UK.
Humnabadkar V iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Mahadevaswamy J iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Vachaspati P iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Sharma S iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Kaur P iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Mallya M iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Rudrapatna S iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Awasthy D iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Sambandamurthy VK iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Pojer F École Polytechnique Fédérale de Lausanne, Global Health Institute, Switzerland.
Cole ST École Polytechnique Fédérale de Lausanne, Global Health Institute, Switzerland.
Balganesh TS iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Ugarkar BG iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Balasubramanian V iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Bandodkar BS iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Panda M iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India.
Ramachandran V iMed Infection, AstraZeneca India Pvt Ltd, Bangalore, India. Electronic address: vasanthi_epr@yahoo.com.

2015-12-09

Published in:

Bioorganic & medicinal chemistry. - 2015

Structure-Activity Relationship

English We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too.

Language

English

Open access status

closed

Identifiers

DOI 10.1016/j.bmc.2015.11.017
PMID 26643218

Persistent URL

https://sonar.ch/global/documents/111852

Statistics

Document views: 13 File downloads:

Journal article

Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose 2'-oxidase.

AMES

Antimycobacterial

Benzothiazoles

DprE1

Genotoxic

Alcohol Oxidoreductases

Antitubercular Agents

Bacterial Proteins

Benzothiazoles

Drug Design

Humans

Molecular Docking Simulation

Mycobacterium tuberculosis

Structure-Activity Relationship

Tuberculosis

Statistics