| Summary: | Based on the heterocyclic core of bendamustine, four series (4a–g, 5a–f, 8a–b and 9a–b) of benzimidazole derivatives were designed and synthesized starting from 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanehydrazide. In the rational design of target molecules, the benzimidazole ring of bendamustine was retained and the bis-(chloroethyl) amine group (mechlorethamine) was substituted with several biologically active scaffolds such as oxadiazole, thiadiazole, and triazolo-thiadiazines, in the hope of obtaining novel cytotoxic agents with improved efficacy and safety. Cytotoxic activities of the designed analogues were carried out at the National Cancer Institute (NCI), USA, against full NCI 60 human cell lines. Among all the tested compounds, 4f (761982/1) exhibited significant antiproliferative activity and was further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 μM) with GI50 values ranging from 0.09 to 16.2 μM and found superior for CNS cancer cell line SNB-75 (GI50 0.09, TGI 1.39, LC50 >100 and log10GI50 −7.0, log10TGI-5.86, log10LC50 >−4.00). Docking study was also performed to provide an insight about the binding mode into binding sites of topoisomerase enzyme. Hopefully in future, compound 4f could be used as a lead compound for developing new anticancer agents. Keywords: Bendamustine, Benzimidazole, Chlorambucil, Sulforhodamine B, Human cell lines
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