A novel series of pyrazole/thiazole chalcone hybrids (9a–o) was designed, synthesized, and evaluated as dual tubulin/COX-2 inhibitors with anticancer activity. The synthesized compounds were screened for antiproliferative activity against MDA-MB-231, HCA-7, and A549 cancer cell lines. Several derivatives exhibited promising activity, with 9m being the most potent against MDA-MB-231 cells (IC50 = 1. 96 ± 0. 10 µM), while 9l emerged as the most balanced lead compound, showing strong antiproliferative activity against HCA-7, MDA-MB-231, and A549 cells with IC₅₀ values of 2. 18 ± 0. 11, 2. 92 ± 0. 15, and 4. 86 ± 0. 25 µM, respectively. Mechanistic studies revealed that the anticancer activity of this series is mediated through a dual mechanism involving tubulin polymerization inhibition and selective COX-2 inhibition. In particular, compound 9l inhibited tubulin polymerization with an IC₅₀ of 4. 21 ± 0. 25 µM and showed potent COX-2 inhibition (IC₅₀ = 0. 10 ± 0. 01 µM) with high selectivity over COX-1 (IC₅₀ = 10. 92 ± 0. 78 µM; selectivity index = 109. 20). Further investigation in HCA-7 cells demonstrated that 9l significantly increased Bax level to 438. 64 ± 15. 72 pg mL^−1 and reduced Bcl-2 to 6. 74 ± 0. 19 pg mL^−1, while markedly elevating caspase-3 and caspase-9 levels to 496. 80 ± 14. 90 pg mL^−1 and 47. 86 ± 1. 18 ng mL^−1, respectively. Moreover, 9l strongly suppressed PGE-2 production to 0. 56 ± 0. 04 ng mL^−1, corresponding to 89. 2% inhibition, and induced G2/M cell-cycle arrest. It also showed promising anti-migratory activity in the wound-healing assay, favorable microsomal stability, and acceptable in silico ADMET properties. Molecular docking further supported its favorable binding within the active sites of both tubulin and COX-2. Collectively, these findings identify 9l as a promising dual tubulin/COX-2-targeting anticancer candidate.
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