8-cyanobenzothiazinone analogs with potent antitubercular activity.

ABSTRACT: 8-Nitrobenzothiazinones (BTZs) exemplified by macozinone are a new class of antitubercular agents with exceptionally potent activity. The aryl nitro group has been considered indispensable for activity since this is bioactivated within mycobacteria by the flavoenzyme DprE1 to a reactive nitroso metabolite that covalently labels Cys387. However, the aryl nitro group is a potential liability with regards to safety, stability, and resistance. In this paper, we introduced a nitrile as a bioisosteric replacement of the nitro group, which we hypothesize can maintain a similar covalent mechanism of inhibition, but mitigate against the aforementioned concerns. 8-cyanobenzothiazinone 1d displayed potent antitubercular activity with an MIC of 130 nM and had an improved volume of distribution

SUBMITTER: Zhang G 

PROVIDER: S-EPMC7805566 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature