Makarov, VadimNeres, JoaoHartkoorn, Ruben C.Ryabova, Olga B.Kazakova, ElenaSarkan, MichalHuszar, StanislavPiton, JeremieKolly, Gaelle S.Vocat, AnthonyConroy, Trent M.Mikusova, KatarinaCole, Stewart T.2015-12-022015-12-022015-12-02201510.1128/Aac.00778-15https://infoscience.epfl.ch/handle/20.500.14299/120928WOS:0003629520000138-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-beta-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 mu g/ml against M. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 mu M 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.text::journal::journal article::research article