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

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ID: 52887
2015
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Abstract
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.
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landge2015discoverybioorganic Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Landge, Sudhir;Mullick, Amrita B;Nagalapur, Kavitha;Neres, João;Subbulakshmi, Venkita;Murugan, Kannan;Ghosh, Anirban;Sadler, Claire;Fellows, Mick D;Humnabadkar, Vaishali;Mahadevaswamy, Jyothi;Vachaspati, Prakash;Sharma, Sreevalli;Kaur, Parvinder;Mallya, Meenakshi;Rudrapatna, Suresh;Awasthy, Disha;Sambandamurthy, Vasan K;Pojer, Florence;Cole, Stewart T;Balganesh, Tanjore S;Ugarkar, Bheemarao G;Balasubramanian, V;Bandodkar, Balachandra S;Panda, Manoranjan;Ramachandran, Vasanthi;
Journal bioorganic & medicinal chemistry
Year 2015
DOI
10.1016/j.bmc.2015.11.017
URL
Keywords
antimycobacterial ames benzothiazoles dpre1 genotoxic

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