Multitarget-directed ligands offer a promising strategy for overcoming tumor complexity through simultaneous modulation of complementary oncogenic pathways. In this work, a novel (E) -6- (3- (4-methyl-2-thioxo-2, 3-dihydrothiazol-5-yl) -3-oxoprop-1-en-1-yl) -2H-chromen-2-one (compound 6) was synthesized and evaluated as a dual inhibitor of tubulin polymerization and tumor-associated carbonic anhydrases (CAs) IX and XII. Compound 6 displayed potent antiproliferative activity, particularly against MDA-MB-231 triple-negative breast cancer cells (IC₅₀ = 0. 37 µM), with excellent selectivity toward non-tumorigenic cells. Mechanistic studies demonstrated strong tubulin polymerization inhibition (IC₅₀ = 3. 40 ± 0. 09 µM) and submicromolar inhibition of CA IX (IC₅₀ = 0. 102 ± 0. 005 µM) and CA XII (IC₅₀ = 0. 213 ± 0. 004 µM), accompanied by downregulation of CA-IX and CA-XII protein expression. Cellular investigations revealed pronounced G2/M phase arrest and apoptosis induction via mitochondrial signaling and caspase activation. Anti-angiogenic activity was supported by inhibition of endothelial migration and concentration-dependent suppression of VEGFR-2 (Tyr1175) phosphorylation in HUVEC cells. Human liver microsomal assays indicated measurable metabolic stability, while molecular docking and in silico ADMET predictions supported target engagement and drug-like properties. Collectively, these findings identify compound 6 as a promising multitarget anticancer lead integrating antimitotic, metabolic, and anti-angiogenic mechanisms.
SALEEM et al. (Thu,) studied this question.