Abstract
Cancer remains a global health challenge with high morbidity and mortality, and the clinical application of conventional anticancer agents is severely limited by issues such as poor selectivity, systemic toxicity, and multidrug resistance. Chalcones, pyridines, and pyrimidines are privileged heterocyclic scaffolds in medicinal chemistry, with inherent anticancer potential, structural flexibility, and good biocompatibility. Molecular hybridization, a rational drug design strategy, has been widely applied to construct chalcone pyridine/pyrimidine hybrids by covalently conjugating these bioactive moieties. These hybrid molecules integrate the dual pharmacological merits of the parent skeletons to produce synergistic anticancer effects and mitigate the drawbacks of single pharmacophore agents. This review summarizes recent advances in anticancer chalcone pyridine/pyrimidine hybrids reported from 2020 to date. We compile 39 hybrid series built on two major scaffold classes: chalcone-pyridine and chalcone-(fused)pyrimidine frameworks. This work focuses on structural design strategies, core structure-activity relationships, and anticancer mechanisms. Major translational bottlenecks are also outlined: most studies rely heavily on cellular level assays, while comprehensive pharmacokinetic, toxicological, and formulation investigations remain insufficient. Finally, current challenges and future research directions for this hybrid class are highlighted, aiming to deliver concise theoretical foundations and practical references for further structural optimization and pre clinical translational study of these promising anticancer lead candidates.