Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis

A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 mu g/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log(10) CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.& nbsp;(c) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

A series of thiophene-benzenesulfonamide derivatives were designed and synthesized to explore their structure-activity relationship as antituberculosis agents. Compound 17b showed improved activity compared to the lead compounds, displaying good intracellular antimycobacterial activity and favorable drug properties.