Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure–activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose 2′-oxidase. Issue 24 (15th December 2015)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 24(2015)
• Page Start: 7694
• Page End: 7710
• Publication Date: 2015-12-15
• Subjects: TB tuberculosis -- Mtb Mycobacterium tuberculosis -- MIC minimal inhibitory concentration -- CYP cytochrome P450 -- SAR structure–activity relationships -- MMIC mammalian cytotoxicity -- DprE1 decaprenylphosphoryl-β-d-ribose 2′-oxidase -- TEA triethylamine -- HCl hydrochloric acid -- PCl3 phosphorous trichloride -- DAST diethylaminosulfurtrifluoride -- DIPEA diisopropylethylamine -- DCM dichloromethane -- HATU 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxid hexafluorophosphate -- ES electrospray ionization -- HRMS high resolution mass spectrometry -- rt room temperature -- RB round bottom -- h hour; Antimycobacterial -- Benzothiazoles -- Genotoxic -- AMES -- DprE1; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.11.017
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.