Curcumin Analogs Containing Pyrazole–Pyridine Hybrids as Novel Anticancer Agents: Synthesis, Cytotoxicity, Apoptosis Induction, and Molecular Modeling

In recent years, curcumin analogs have not only demonstrated potent anticancer activities but have also addressed several limitations of curcumin itself, thereby remaining a promising focus of research within the scientific community. Building upon the findings of our previous studies, structural modifications of potent curcumin analogs fused with 1 H ‐pyrazole are performed by applying the bioisosteric replacement strategy of a benzene ring with a pyridine ring, to develop a series of novel curcumin analogs containing pyrazole–pyridine hybrids ( 3a –4h ) as promising anticancer agents. Among them, curcumin analog 4c emerges as the most potent compound, exhibiting the strongest cytotoxicity against various human cancer cell lines, including HepG2 (liver), MDA‐MB‐231 (breast), and A549 (lung), as well as significant apoptosis‐inducing effects in HepG2 cells. Furthermore, compound 4c is predicted to possess a favorable physicochemical–pharmacokinetic–toxicological profile, as well as an effective binding mode at the colchicine‐binding site of the α , β ‐tubulin heterodimer. Importantly, the bioisosteric replacement in compound 4c is found to exert beneficial effects on its anticancer activities, physicochemical–pharmacokinetic–toxicological properties, and binding affinity, in comparison with its parent compounds.