title: The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: More Medicines for Tuberculosis Consortium‡ A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Vadim
authors.initials: V
authors.lastname: Makarov
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Hartkoorn
authors.affiliation: More Medicines for Tuberculosis Consortium‡ A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Ryabova
authors.affiliation: More Medicines for Tuberculosis Consortium‡ A. N. Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Kazakova
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Šarkan
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Huszár
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Piton
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Gaëlle S
authors.initials: GS
authors.lastname: Kolly
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Anthony
authors.initials: A
authors.lastname: Vocat
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Conroy
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.
authors.forename: Katarína
authors.initials: K
authors.lastname: Mikušová
authors.affiliation: More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland stewart.cole@epfl.ch.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain / Q000187:drug effects; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy / Q000378:metabolism
chemical_list: C540716:2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; C557081:2-pyridin-2-yl-4H-1,3-benzothiazin-4-one; C582660:3-(6-(4-oxo-4H-1,3-benzothiazin-2-yl)pyridin-2-yl)propanoic acid; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010879:Piperazines; D011725:Pyridines; D011758:Pyrroles; D013141:Spiro Compounds; D013843:Thiazines; C000592783:macozinone; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis