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

Phenotypic screening
of a Medicines for Malaria Venture compound
library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones.
The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds
were bactericidal against replicating Mtb and retained
potency against clinical isolates of Mtb. Although
selected MmpL3 mutant strains of Mtb 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 in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity
against mammalian cell lines.