%0 Journal Article %A Makarov, Vadim %A Neres, João %A Hartkoorn, Ruben C. %A Ryabova, Olga B. %A Kazakova, Elena %A Šarkan, Michal %A Huszár, Stanislav %A Piton, Jérémie %A Kolly, Gaëlle S. %A Vocat, Anthony %A Conroy, Trent M. %A Mikušová, Katarína %A Cole, Stewart T. %T The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis %D 2015 %R 10.1128/AAC.00778-15 %J Antimicrobial Agents and Chemotherapy %P 4446-4452 %V 59 %N 8 %X 8-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. %U https://aac.asm.org/content/aac/59/8/4446.full.pdf