Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

Abstract

Benzothiazinones are promising candidates in the fight against tuberculosis, the leading bacterial killer worldwide. We present an overview of recent developments in the field of antitubercular benzothiazinones and summarize our own contributions.

A Review of Antibacterial Candidates with New Modes of Action

“…The additional O-propanol and aminomethylene groups present in epetraborole (72) compared to tavaborole (71) enhance its binding to bacterial leucyl-tRNA synthetases and its antibacterial activity. 266,273 There has also been a recent report investigating the OBORT mechanism for ganfeborole (73), which showed that it could form a highly specific and reversible LeuRS inhibition adduct with ATP, AMP, and the terminal tRNA adenosine. 277 The study employed NMR, X-ray crystallography, and SPR to show that one of the two ganfeborole−AMP adducts (74) preferentially bound to the active site.…”

“…Another cell envelope target is decaprenylphosphoryl-β- d -ribose (DPR) 2′-oxidase (DprE1), a critical enzyme in the biosynthesis of arabinogalactan and lipoarabinomannan, which are key components of the mycobacterial cell wall. The extracytoplasmic location of DprE1 enhances the ability of inhibitors to reach their target. , In 2006, a series of dialkyldithiocarbamate derivatives were reported to have antimycobacterial activity, and further optimization led to the identification of a benzothiazinone, BTZ-043 ( 10 ), − with in vivo TB activity . MoA studies showed that the BTZs underwent in vivo reduction of the nitro group, then formed a semimercaptal covalent bond with cysteine-387 of DprE1. − A phase 2 trial (NCT05926466) evaluating three BTZ-043 ( 10 )-containing TB drug regimens started in September 2023.…”