Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

Tuberculosis is the leading bacterial killer worldwide. 8-Nitro-4H-benzo[e][1,3]thiazin-4-ones are a potent class of antitubercular agents with a new mechanism of action. BTZ043 and PBTZ169 (macozinone) have progressed to clinical studies. Herein, we give a comprehensive account of this important class of potential new drugs to treat tuberculosis. We present an overview of recent developments in the field of antitubercular benzothiazinones (BTZs) and summarize our own contributions. The review covers synthesis, structures and reactivity, mechanism of action, in vitro activity and structure activity relationships (SARs), physicochemical and pharmacokinetic properties as well as a brief summary of in vivo models and clinical studies. We address bioavailability issues and the challenge of the potentially toxic nitroaromatic moiety, including reactivity towards nucleophiles in vivo and highlight possible directions of further research into BTZs through chemical modification.

Automated summary

This article provides a comprehensive account of a potential new class of drugs for tuberculosis treatment called 8-nitro-4H-benzo[e][1,3]thiazin-4-ones. These compounds are potent antitubercular agents with a novel mechanism of action. The review includes synthesis, structures and reactivity, mechanism of action, in vitro activity and structure-activity relationships, as well as physicochemical and pharmacokinetic properties. It also summarizes in vivo models and clinical studies, addressing bioavailability issues and the challenge of potentially toxic nitroaromatic moiety, and suggests possible directions for further research through chemical modification.