Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis.
Zhao H, Gao Y, Li W, Sheng L, Cui K, Wang B, Fu L, Gao M, Lin Z, Zou X, Jackson M, Huang H, Lu Y, Zhang D.
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 (IC<sub>50</sub> > 64 μg/mL). Compound <b>32</b> displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K<sup>+</sup> channel, and good <i>in vivo</i> efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their potency against <i>M. smegmatis</i> expressing wild-type and mutated variants of the <i>mmpL3</i> gene from <i>M. tuberculosis</i> (<i>mmpL3tb</i>) and determining their effect on mycolic acid biosynthesis using a [<sup>14</sup>C] acetate metabolic labeling assay. The present study provides new MmpL3 inhibitors that are promising anti-TB agents.