Imidazopyridines as anticancer chemotypes: Structure-activity relationships, molecular targets, and lead optimization opportunities

Cancer is multifactorial in nature and has been regarded as a leading cause of death worldwide. Imidazopyridine has emerged as a privileged scaffold for expanding the chemical space toward the generation of novel anticancer lead molecules with improved physicochemical and drug-like properties. This review highlights the recent advancements over the past four years in the rational design and development of imidazopyridine scaffold-based derivatives for the generation of potential anticancer agents. Emphasis has been placed on comparative structure-activity relationships (SAR), recurring structural features across different molecular targets, molecular docking analysis, and the determination of IC₅₀ values. Imidazopyridine-based derivatives have exhibited significant anticancer activity by targeting various biomarkers and signaling pathways, including the inhibition of protein kinases, disruption of tubulin polymerization, inhibition of DNA topoisomerases and estrogen receptor alpha, modulation of histone deacetylases, interference with the DNA replication machinery, induction of apoptosis, and arrest of cell-cycle progression. ADMET and physicochemical profiling revealed that compounds 41, 107, 111, 116, and 122 possessed desirable predicted physicochemical and favorable ADMET properties. Further structural optimization and experimental validation of compounds 41, 107, 111, 116, and 122, which exhibited favorable predicted physicochemical and ADMET profiles, may help determine their potential as anticancer candidates against their respective molecular targets.