Optimization of pyrrole-2-carboxamide to develop a potent antituberculosis agent with improved physicochemical property and druggability.

MmpL3, a mycobacterial membrane protein, is essential for the transport of trehalose monomycolate, which is crucial for the formation of the M. tuberculosis outer membrane and the survival of the bacterium. Herein, we optimize our lead MmpL3 inhibitor bearing pyrrole-2-carboxamide scaffold to develop antituberculosis agents with improved physicochemical properties. Compound 27b, an optimized analog of our lead MmpL3 inhibitor, exhibited enhanced antituberculosis activity along with reduced cytotoxicity, improved microsomal stability, and high Caco-2 permeability. Significantly, the water solubility and pharmacokinetic profile of compound 27b was markedly improved compared to the lead compound 2. This compound demonstrated potent efficacy in decreasing the intracellular M. tuberculosis load within mouse macrophages. The results of this study indicated that incorporating an oxygen-containing group in pyrrole-2-carboxamide scaffold can improve the compound's LogP value, thereby achieving a balance between lipophilicity and antituberculosis activity.