Several studies have indicated the potential therapeutic outcomes of combining selective COX-2 inhibitors with tubulin-targeting anticancer agents. In the current study, a novel series of thiazolidin-4-one-based derivatives (7a–q) was designed by merging the pharmacophoric features of some COXs inhibitors and tubulin polymerization inhibitors. Compounds 7a–q were synthesized and evaluated for their cytotoxic activity against MCF7, HT29, and A2780 cancer cell lines (IC₅₀ = 0.02–17.02 μM). The cytotoxicity of 7a–q was also assessed against normal MRC5 cells (IC₅₀ = 0.47–13.46 μM). Compounds 7c, 7i, and 7j, the most active in the MTT assay, significantly reduced the number of HT29 colonies compared to the control. Compounds 7c, 7i, and 7j also induced significant decreases in the tumor volumes and masses in Ehrlich solid carcinoma-bearing mice compared to the control. The three compounds

A small set of indole-based derivatives, IV and Va–I, was designed and synthesized. Compounds Va–i demonstrated promising antiproliferative activity, with GI₅₀ values ranging from 26 nM to 86 nM compared to erlotinib’s 33 nM. The most potent antiproliferative derivatives—Va, Ve, Vf, Vg, and Vh—were tested for EGFR inhibitory activity. Compound Va demonstrated the highest inhibitory activity against EGFR with an IC₅₀ value of 71 ± 06 nM, which is higher than the reference erlotinib (IC₅₀ = 80 ± 05 nM). Compounds Va, Ve, Vf, Vg, and Vh were further tested for BRAF^V600E inhibitory activity. The tested compounds inhibited BRAF^V600E with IC₅₀ values ranging from 77 nM to 107 nM compared to erlotinib’s IC₅₀ value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAF^V600E, and VEGFR-2.