Design, synthesis, and biological evaluation of quinolin-2-one/thiazole hybrids as multi-targeted antiproliferative...

A novel series of quinolin-2-one/thiazole hybrids (6a-l) was designed, synthesized, characterized, and evaluated for their in vitro antiproliferative efficacy against three human cancer cell lines: HCT-116, MCF-7, and HepG-2. Most derivatives demonstrated good-to-moderate cytotoxic profiles. Among them, compound 6b emerged as the most potent lead candidate, with a mean IC₅₀ of 4.20 µM, representing a 1.7-fold higher potency than the reference drug, sorafenib (IC₅₀ = 6.80 µM). Specifically, compound 6b exhibited enhanced cytotoxicity against HCT-116 (IC₅₀ = 5.20 µM) and MCF-7 (IC₅₀ = 4.20 µM), and a two-fold higher potency against HepG-2 (IC₅₀ = 3.20 µM) cells compared to sorafenib. Enzymatic assays revealed that 6b acts as an efficient multi-kinase inhibitor, effectively targeting EGFR (IC₅₀ = 0.058 µM) and HER-2 (IC₅₀ = 0.060 µM) with potencies comparable or superior to the standard controls erlotinib and lapatinib, while moderately inhibiting VEGFR-2 (IC₅₀ = 0.51 µM). Safety screening against normal WI-38 cells showed low cytotoxicity (IC₅₀ = 51.21 µM) and outstanding selectivity indices (SI > 10, > 12, and 16) for HCT-116, MCF-7, and HepG-2, respectively. Mechanistic investigations in HepG-2 cells confirmed that 6b induced a 6.9-fold increase in caspase-3/7 activity, triggering significant apoptosis. SAR analysis highlighted that a 6-methyl substitution on the quinoline core, an unsubstituted N-1 position, and a bulky 3-phenyl group on the thiazole ring are key structural prerequisites for optimal anticancer activity. These findings, along with docking investigation, highlight compound 6b as a promising multi-kinase therapeutic scaffold for further targeted oncological optimization.