8-cyanobenzothiazinone analogs with potent antitubercular activity

Gang Zhang, Li Sheng, Pooja Hegde, Yan Li, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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 in mice that increased the intrinsic half-life by twofold compared to macozinone. Analysis of the C-2 substituent of 1d revealed similar structure-activity relationships as observed for macozinone. Overall, the results confirm the 8-nitro group of benzothiazinones can be successfully replaced with a nitrile to retain useful activity and favorable pharmacokinetic properties.

Original languageEnglish (US)
Pages (from-to)449-458
Number of pages10
JournalMedicinal Chemistry Research
Issue number2
Early online dateJan 13 2021
StatePublished - Feb 2021

Bibliographical note

Funding Information:
This work was financially supported by a grant from the CAMS Innovation Fund for Medical Sciences (CAMS-2017-I2M-1-011).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.


Dive into the research topics of '8-cyanobenzothiazinone analogs with potent antitubercular activity'. Together they form a unique fingerprint.

Cite this