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

Autor: 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.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Dec 15; Vol. 23 (24), pp. 7694-710. Date of Electronic Publication: 2015 Nov 18.
DOI: 10.1016/j.bmc.2015.11.017
Abstrakt: 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.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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