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 1H-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.