N-substituted benzimidazole acrylonitriles as in vitro tubulin polymerization inhibitors: Synthesis, biological activity and computational analysis

We present the design, synthesis and biological activity of novel N-substituted benzimidazole based acrylonitriles as potential tubulin polymerization inhibitors. Their was achieved using classical linear organic microwave assisted techniques, starting from aromatic aldehydes N-substituted-2-cyanomethylbenzimidazoles. All newly prepared compounds were tested for their antiproliferative in vitro on eight human cancer cell lines one reference non-cancerous assay. N,N-dimethylamino substituted 30 41, bearing N-isobutyl cyano substituents placed nuclei, showed strong selective submicromolar range inhibitory concentrations (IC50 0.2–0.6 ?M), while being significantly less toxic than systems docetaxel staurosporine, thus promoting them lead compounds. Mechanism action studies demonstrated that two most active inhibited polymerization. Computational analysis confirmed suitability employed benzimidazole-acrylonitrile skeleton binding within colchicine site tubulin, rationalizing observed antitumor activities, E-isomers are substances. It also provided structural determinants affecting both position matching affinities, identifying attached NMe2 group dominant binding, which allows ligands to optimize favourable cation???? hydrogen bonding interactions with Lys352.