Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies.

Phenotypic screening of a Medicines for Malaria Venture compound library against () identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of suggested a novel mechanism of action. The compounds were bactericidal against replicating and retained potency against clinical isolates of . Although selected MmpL3 mutant strains of showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.