Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-D-ribose 2'-oxidase.
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.
['Landge|Sudhir|S|', 'Mullick|Amrita B|AB|', 'Nagalapur|Kavitha|K|', 'Neres|João|J|', 'Subbulakshmi|Venkita|V|', 'Murugan|Kannan|K|', 'Ghosh|Anirban|A|', 'Sadler|Claire|C|', 'Fellows|Mick D|MD|', 'Humnabadkar|Vaishali|V|', 'Mahadevaswamy|Jyothi|J|', 'Vachaspati|Prakash|P|', 'Sharma|Sreevalli|S|', 'Kaur|Parvinder|P|', 'Mallya|Meenakshi|M|', 'Rudrapatna|Suresh|S|', 'Awasthy|Disha|D|', 'Sambandamurthy|Vasan K|VK|', 'Pojer|Florence|F|', 'Cole|Stewart T|ST|', 'Balganesh|Tanjore S|TS|', 'Ugarkar|Bheemarao G|BG|', 'Balasubramanian|V|V|', 'Bandodkar|Balachandra S|BS|', 'Panda|Manoranjan|M|', 'Ramachandran|Vasanthi|V|']
D000429:Alcohol Oxidoreductases D000995:Antitubercular Agents D001426:Bacterial Proteins D052160:Benzothiazoles D015195:Drug Design D006801:Humans D062105:Molecular Docking Simulation D009169:Mycobacterium tuberculosis D013329:Structure-Activity Relationship D014376:Tuberculosis
Benzothiazoles Antimycobacterial DprE1 Genotoxic AMES