8-cyanobenzothiazinone analogs with potent antitubercular activity

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 meta...

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Bibliographic Details
Published in:Medicinal chemistry research 2021, Vol.30 (2), p.449-458
Main Authors: Zhang, Gang, Sheng, Li, Hegde, Pooja, Li, Yan, Aldrich, Courtney C.
Format: Article
Language:English
Subjects:
Antitubercular agents
Aromatic compounds
Biochemistry
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Inorganic Chemistry
Liability
Medicinal Chemistry
Metabolites
Original Research
Pharmacokinetics
Pharmacology/Toxicology
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Summary: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.
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-020-02676-4