Abstract A series of 30 small hybrid molecules are synthesized inspired from Combretastatin A-4 (CA-4), where ethylene-bridge of CA-4 is replaced with two five-membered heterocyclic rings, viz. isoxazoline and 1, 2, 3-triazole. These are joined by a methylene linker, with substitutions at A and B ? ring position of CA-4. The new molecular entities have shown significant cytotoxicity to cancer cell from the IC50 0.49??M?3.17??M with 1-((4,5-Dihydro-3-(2,5-dimethoxyphenyl)isoxazol-5-yl)methyl)-4-(4-methoxyphenyl)-1H-1,2,3-triazole displayed IC50 0.422±0.07??M for A-549 -lung cancer cell line and IC50 0.498±0.03??M for MDA-MB-231-breast cancer cell line. The western blot analysis, confocal staining and also by in?vitro tubulin polymerization assay established the target specificity of the molecules as a tubulin polymerization inhibitor. Molecular docking & Molecular dynamics studies confirmed the binding interaction patterns of these molecules at the Colchicine binding site of tubulin and have correlated the observed experimental result with variation in structure satisfactorily.