Nature-inspired chalcone-functionalized paracetamol derivatives as potential anticancer leads: synthesis, biological evaluation, apoptotic mechanisms, and in silico docking studies

Inspired by the known Anticancer activities of hydroxychalcones and acetamidochalcones, a series of novel hybrid molecules integrating these motifs with a paracetamol core were designed and synthesized. The synthesized chalcone-paracetamol hybrids were evaluated for their antiproliferative activity against a panel of eight human Cancer cell lines. Compounds 6a, 6b, and 9, showed good activity against four Cancer cell lines (U937, Jurkat, HCT-116 and MCF-7 cells). Notably, derivative 9 was the most potent with IC₅₀ ranging from 1.50 to 4.50 μM, while showing no significant toxicity toward normal cells. Mechanistic investigations revealed that compound 9 induced cell cycle arrest at G0/G1 phase and stimulated Apoptosis. Further biochemical analysis identified it (9) as a multi-target agent, with significant inhibitory activity against EGFR (0.62 ± 0.02 μM), VEGFR-2 (2.26 ± 0.01 μM), COX-2 (17.38 ± 0.13 μM), and tubulin polymerization (19.31 ± 0.29 μM). Molecular docking analysis supported these results, showing strong binding affinities for the respective target proteins, with high binding scores of compound 9 ranging from (-9.2 to -10.0) kcal/mol. Collectively, these findings highlight that compound 9 is worthy of further investigation as a potential Anticancer lead.