Indole-based carbohydrazides as potent anti-proliferative leads and tubulin polymerization inhibitors: design, synthesis, cytotoxic evaluation, in silico ADMET and docking studies

Aims A novel series of indolecarbohydrazide derivatives (3a-r) was designed and synthesized to evaluate their potential as tubulin polymerization inhibitors and selective anticancer agents.Materials and methods The cytotoxic potential of compounds 3a-r was assessed against six human cancer cell lines and nonmalignant RPE-1 cells. Mechanistic studies included tubulin polymerization assays, cell cycle analysis, and apoptosis induction. Pharmacokinetic profiles were predicted using SwissADME, while molecular docking (MOE-Dock v2024.0601) explored binding affinities at the colchicine site.Results Compounds 3b, 3d, 3i, and 3p showed significant potency against MCF-7 cells, with 3i being the most active (IC50 = 1.0 ± 0.05 mM), outperforming doxorubicin. Derivatives 3d and 3i effectively inhibited tubulin polymerization (IC50 = 3.96 and 6.28 μM, respectively), comparable to combretastatin A4. Compound 3d induced G2/M phase arrest and apoptosis, consistent with microtubule disruption. In silico analysis predicted favorable drug-like properties, and docking scores (−9.28 to −10.92 kcal/mol) confirmed high affinity for the colchicine binding site.Conclusions These findings identify the indolecarbohydrazide scaffold as a potent anti-proliferative lead that successfully disrupts tubulin dynamics, offering a promising foundation for further development of colchicine-site microtubule-targeting agents.