Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility

Nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents targeting DprE1. Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds <bold>1a</bold> and <bold>3</bold> were first reported to possess excellent activity against MTB H(37)Rv and MDR-MTB strains (MIC: <0.029-0.095 mu M), low toxicity and acceptable oral PK profiles, as well as significantly improved water solubility (1200 and > 2000 mu g/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery.