Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors

Abdullaziz, M. A., H. T. Abdel-Mohsen, A. M. El Kerdawy, F. A. F. Ragab, M. M. Ali, S. M. Abu-bakr, A. S. Girgis, and H. I. El Diwani, "Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors", Eur. J. Med. Chem., vol. 136, pp. 315 - 329, 2017/8/18/.


AbstractInhibition of angiogenesis through inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) has been applied in cancer therapy because of its important role in promoting cancer growth and metastasis. In the presented study, a series of benzimidazol-furan hybrids was designed and synthesized through facile synthetic pathways. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines was performed. Two of the synthesized conjugates, 10b and 15, showed potent antiproliferative properties against MCF-7 cell line (IC50 = 21.25, 21.35 μM, respectively) in comparison to tamoxifen (IC50 = 21.57 μM). Additionally, compounds 10a, 10b, 15 and 17 showed promising potency (IC50 = 25.95, 22.58, 26.94 and 31.06 μM, respectively) against liver carcinoma cell line HepG2 in contrast to cisplatin (IC50 = 31.16 μM). Moreover, in vitro evaluation of the synthesized compounds for their effect on the level of VEGFR-2 in MCF-7 cell line showed their potent inhibitory activity relative to control untreated cells. Four compounds 10a, 10b, 14 and 15 showed 92–96% reduction in VEGFR-2 level, compared with tamoxifen and sorafenib which showed inhibition percentage of 98% and 95.75%, respectively. Compound 10a was found to have promising VEGFR-2 inhibitory activity (IC50 = 0.64 μM) in comparison to sorafenib (IC50 = 0.1 μM). Molecular docking was performed to study the binding pattern of the newly synthesized compounds with VEGFR-2 active site. Molecular docking attributed their good VEGFR-2 inhibitory activity to their hydrogen bonding interaction with the key amino acids in VEGFR-2 active site, Glu885 and Asp1046, and their hydrophobic interaction by their 2-furylbenzimidazole moiety with the allosteric hydrophobic back pocket in a type III inhibitors-like binding mode. The binding interaction is augmented by a ring substituent with long chain extension at position 1 of the benzimidazole due to its hydrophobic interaction with the hydrophobic side chains of the amino acids at the interface between the ATP binding site and the allosteric back pocket. Structure-activity relationship (SAR) was inferred for future optimization based on the performed biological and docking studies.



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