• Vadim Makarov, João Neres, Ruben C Hartkoorn, Olga B Ryabova, Elena Kazakova, Michal Šarkan, Stanislav Huszár, Jérémie Piton, Gaëlle S Kolly, Anthony Vocat, Trent M Conroy, Katarína Mikušová, and Stewart T Cole.
• More Medicines for Tuberculosis Consortium‡ A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia.
• Antimicrob. Agents Chemother. 2015 Aug 1; 59 (8): 4446-52.

Abstract8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml against M. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 μM and present favorable in vitro absorption-distribution-metabolism-excretion/toxicity (ADME/T) and in vivo pharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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