(E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides as tubulin polymerization inhibitors: Structure-based bioisosterism design,synthesis, biological evaluation,molecular docking and in silico ADME prediction

A series of (E)-N-Aryl-2-oxo-2-(3,4,5-trimethoxyphenyl)acetohydrazonoyl cyanides have been synthesized and evaluated for their anticancer activity in human hepatocellular liver carcinoma HepG2 and breast adenocarcinoma MCF-7?cell lines. Among all the tested compounds, compound 3a, 3e and 3n displayed more activity than lead compound with IC₅₀ value of 0.26–0.61?μM. Meanwhile, these compounds (3a, 3e and 3n) showed potent antiproliferative activity against a panel of cancer cells and the HCT-8/T multidrug resistant cell line with IC₅₀ values in the range of 0.077– 7.44?μM. Flow cytometric analyses revealed that compound 3n induced cell cycle arrest in G2/M phases in a dose dependent manner. The compound 3n also displayed potent tubulin polymerization inhibition with an IC₅₀ value of 0.9?µM, with ten folds more active than colchicine (IC₅₀?=?9?μM). Molecular docking studies revealed that compound 3n efficiently interacted with the colchicine binding site of tubulin through hydrophobic, cation-π and hydrogen bond interaction. Furthermore, in silico pharmacokinetic prediction shown that these compounds have a good ADME-related physicochemical parameters. These results demonstrate that 3n exhibits potent cytotoxicity in cancer cells by targeting the colchicine binding site of tubulin and potentially acts as a therapeutic lead compound for the development of anticancer drugs.