Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis.

ABSTRACT: In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure-activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC < 0.016 μg/mL) and low cytotoxicity (IC₅₀ > 64 μg/mL). Compound 32 displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K⁺ channel, and good in vivo efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their po

SUBMITTER: Zhao H 

PROVIDER: S-EPMC9379527 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature