The 6-trifluoro substituted 8-nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents, and their high antimycobacterial activity is related to the inhibition of decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1), an enzyme essential for the biosynthesis of mycobacterial cell wall. While extraordinary whole-cell activity was reported for the clinically advanced compound PBTZ169, its poor aqueous solubility signals the potential low bioavailability. To ameliorate the BTZ physiochemical property, a series of 6-methanesulfonyl substituted compounds were designed and prepared, and their antitubercular activity and DprE1 inhibition ability were evaluated. Among these compounds, MsPBTZ169 and compounds 2 and 8 exhibited minimum inhibitory concentrations (MICs) of less than 40 nM; moreover, these compounds displayed increased aqueous solubility and acceptable metabolic stability. Taken together, this study suggested that the 6-methanesulfonyl substituted 8-nitrobenzothiazinone derivatives, in combination with side chain modification, might provide BTZ type antitubercular agents with improved drug-like properties.
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