Design, Synthesis, and Biological Evaluation of Triazole Tethered Coumarin-Indole Fused Chalcone-Isatin Derivatives as a New Class of Anti-Breast Cancer Agents.

Inspired by the anti-breast cancer and anti-tubulin potential of coumarin, indole, chalcone, and isatin moieties, a new series of triazole-tethered coumarin-fused chalcone and isatin hybrids were designed, synthesized, and evaluated for their anti-breast cancer activities. Among the series of hybrid compounds, JKUB2 showed the strongest activity against MCF-7 breast cancer cells with an IC50 value of 1.28 µM. JKUB2 exhibited tubulin polymerization inhibition potential (IC50 = 1.31 µM) and induced apoptosis in breast cancer cells by arresting the cell cycle at the G2/M phase. Apart from that, JKUB2 showed higher selectivity (selectivity index: 6.36) toward MCF-7 cells over normal skin fibroblast cells (L929). Morphological studies further confirmed the capability of JKUB2 to induce cell death via apoptotic pathways. Molecular docking and dynamics simulations studies confirmed the desired interactions of JKUB2 in the colchicine binding site of microtubules, responsible for their polymerization inhibition. Overall, the study represents JKUB2 as a potential anti-breast cancer agent that acts via tubulin polymerization inhibition and induces cell death by apoptotic pathways, and warrants further research as well as acts as an effective hit lead for further development of potent and safer anti-breast cancer agents.