Evaluation of the in vivo efficacy of novel monosubstituted sulfonylureas against H37Rv and extensively drug-resistant tuberculosis.

Sulfonylureas have been regarded as potential drug candidates against tuberculosis (TB) because they can inhibit the biosynthesis of branched-chain amino acids by targeting acetohydroxyacid synthase (AHAS). We demonstrated previously that novel monosubstituted sulfonylureas showed potent in vitro activities against TB. In the current study, we further explored the anti-TB activity of monosubstituted sulfonylureas in a mouse model. Compounds 30 and 31 exhibited the most efficacy: a single intragastric administration at a dose of 250 mg/kg led to a reduced lung bacterial count, and the dose of 500 mg/kg achieved a >99% reduction in bacterial load for both H37Rv and extensively drug-resistant isolates. These results indicate that these compounds are more potent than commercial sulfonylureas in vivo and may provide insight into the potential implications for the design of novel drugs to combat TB by targeting AHAS.