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-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 DprE1 and is BTZ043 resistant) unequivocally indicated that BTZ-N 3 is an effective reversible and noncovalent inhibitor of DprE1.

Learning from the past for TB drug discovery in the future

“…Interestingly, the amino derivative BTZ045 acted as an efficient noncovalent inhibitor of DprE1 with an IC 50 value similar to BTZ043 in these assays [43], although essentially no activity of this compound was observed in the crude assay [36]. These observations are comparable with recent studies by Tiwari et al , who evaluated a BTZ043 analog with the azido-group instead of nitro-group in the 8 position [44]. Although BTZ-N 3 was an efficient reversible and noncovalent inhibitor of DprE1 with IC 50 9.6 ±0.5 μM in the assay with DCPIP, which is similar to other BTZs [43], examination of its effects in the crude assay did not show any inhibition of DPA production even at a rather high concentration of the compound (100 μg/ml).…”

cine- and tele-Substitution reactions: review of work from 2002-2016

“…Miller et al have recently published a paper 22 in which they used the term "cine addition" for the chemical reduction of nitro to nitroso group in an aromatic compound (BZT) by the action of the thiolate anion (Scheme 9). The term cine was used to indicate the location of an attack of the thiolate anion on the ortho position to the reduced nitro group in BZT.…”

Antitubercular activity of 1,2,3-triazolyl fatty acid derivatives

“…The products were characterized by 1D-, 2D- NMR experiments, IR and HRMS, displaying a 1,4-substitution pattern as was expected based our previous experience[18, 37] and by several other reports. [42, 43]…”