Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 7, Issue 3, Pages 266-270Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.5b00424
Keywords
BTZ043; DprEI; BTZ-N-3; 1,3-Benzothiazinone azide; Mycobacterium smegmatis; Mycobacterium tuberculosis; tuberculosis
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Funding
- National Institutes of Health (NIH) [2R01AI054193]
- National Science Foundation (NSF) [CHE-0741793]
- European Community [260872]
- Slovak Research and Development Agency [DO7RP-0015-11]
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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-N-3) and related click chemistry products based on the molecular mode of activation of BTZ043. Our computational docking studies indicate that BTZ-N-3 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 DprEl and is BTZ043 resistant) unequivocally indicated that BTZ-N3 is an effective reversible and noncovalent inhibitor of DprEl.
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