title: Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043.
abstract: Electron deficient nitroaromatic compounds such as BTZ043 and its closest congener, PBTZ169, and related agents are a promising new class of anti-TB compounds. Herein we report the design and syntheses of 1,3-benzothiazinone azide (BTZ-N3) and related click chemistry products based on the molecular mode of activation of BTZ043. Our computational docking studies indicate that BTZ-N3 binds in the essentially same pocket as that of BTZ043. Detailed biochemical studies with cell envelope enzyme fractions of Mycobacterium smegmatis combined with our model biochemical reactivity studies with nucleophiles indicated that, in contrast to BTZ043, the azide analogue may have a different mode of activation for anti-TB activity. Subsequent enzymatic studies with recombinant DprE1 from Mtb followed by MIC determination in NTB1 strain of Mtb (harboring Cys387Ser mutation in DprE1 and is BTZ043 resistant) unequivocally indicated that BTZ-N3 is an effective reversible and noncovalent inhibitor of DprE1.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
authors.forename: Rohit
authors.initials: R
authors.lastname: Tiwari
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Miller
authors.affiliation: Department of Biology and Biotechnology, University of Pavia , 27100 Pavia, Italy.
authors.forename: Laurent R
authors.initials: LR
authors.lastname: Chiarelli
authors.affiliation: Department of Biology and Biotechnology, University of Pavia , 27100 Pavia, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mori
authors.affiliation: Department of Biochemistry, Faculty of Natural Sciences, Comenius University , Mlynská dolina, 84215 Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Šarkan
authors.affiliation: Department of Biochemistry, Faculty of Natural Sciences, Comenius University , Mlynská dolina, 84215 Bratislava, Slovakia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Centárová
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, Faculty of Natural Sciences, Comenius University , Mlynská dolina, 84215 Bratislava, Slovakia.
authors.forename: Katarína
authors.initials: K
authors.lastname: Mikušová
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
authors.forename: Allen G
authors.initials: AG
authors.lastname: Oliver
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
keywords: 1,3-Benzothiazinone azide; BTZ-N3; BTZ043; DprE1; Mycobacterium smegmatis; Mycobacterium tuberculosis; tuberculosis