Benzothiazinones

Benzothiazinones are a class of heterocyclic compounds characterized by a benzene ring fused to a thiazinone ring, frequently bearing a nitro group at a key position. They have attracted interest as potential antitubercular agents due to inhibition of DprE1, an essential enzyme in Mycobacterium tuberculosis involved in the synthesis of the arabinan component of the cell wall.

Most benzothiazinones act as nitroaromatic prodrugs. In bacteria, the nitro group is reduced by nitroreductases to reactive intermediates that can form covalent interactions with DprE1, effectively inactivating the enzyme and disrupting cell-wall formation. This mechanism underpins potent in vitro activity against M. tuberculosis, including some drug-resistant strains, but also raises concerns about safety and metabolic liabilities.

A representative member of the class is BTZ043, and numerous analogs (often referred to as PBTZ derivatives) have been reported to explore structure–activity relationships, aiming to improve potency, selectivity, and pharmacokinetic properties. Despite strong preclinical activity, no benzothiazinone compound has achieved clinical approval to date. Development has been limited by issues such as toxicity concerns, variable metabolic stability, and potential resistance arising from alterations in nitroreductase activity or DprE1 itself. Ongoing research seeks to optimize the balance between bactericidal efficacy and safety, as well as to broaden activity and delivery options.

Synthesis generally centers on constructing the benzothiazinone core, with installation of a nitro group and diversification of substituents to tune potency and pharmacokinetic characteristics. The class remains of interest for antitubercular drug discovery and related antibacterial applications.

See also: DprE1 inhibitors, nitroaromatic prodrugs, BTZ043.