Colchicine binds to tubulin and destabilizes microtubules, stopping cell division and causing apoptosis. Its anti-cancer property affects microtubule integrity despite its reported toxicity. A series of novel colchicine derivatives were synthesized using the multi-component reaction method and evaluated for their antiproliferative properties, aiming to enhance their efficacy as anti-cancer agents compared to the parent compound, colchicine. With the SRB assay, we tested these derivatives for their anti-cancer efficacy against lung, breast, and melanoma using several human cancer cell lines, including A549, MCF-7, MDAMB-231, and A375. The study identified a derivative, , as notably more effective against melanoma cells, with a selectivity index about two times higher than colchicine. We further investigated the anti-cancer efficacy of compound on human melanoma cells using additional models, including the wound healing assay and colony formation assay. Compound inhibited colony formation by up to 62.5% and reduced the migration potential of melanoma cells by 69%. The studies reveal the probable interactions with the colchicine binding sites that have a comparable pose to colchicine. formed a hydrogen bond with Cys241, Asn258 and a salt bridge with Lys352, which is important for its tubulin polymerization inhibitory activity. These findings suggest that could selectively target melanoma cells, minimizing toxicity to healthy cells and potentially providing a safer and more effective treatment option with improved therapeutic outcomes.