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

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

  • Eur J Med Chem. 2017 Aug 18:136:315-329. doi: 10.1016/j.ejmech.2017.04.068.
Mona A Abdullaziz 1,  Heba T Abdel-Mohsen 2,  Ahmed M El Kerdawy 3,  Fatma A F Ragab 4,  Mamdouh M Ali 5,  Sherifa M Abu-Bakr 1,  Adel S Girgis 6,  Hoda I El Diwani 1
Affiliations

Affiliations

  • 1 Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Dokki, Cairo, Egypt.
  • 2 Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Dokki, Cairo, Egypt. Electronic address: hebabdelmohsen@gmail.com.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
  • 5 Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, Egypt.
  • 6 Department of Pesticide Chemistry, Division of Chemical Industries Research, National Research Centre, Cairo, Egypt.
PMID: 28505536 DOI: 10.1016/j.ejmech.2017.04.068
Abstract

Inhibition 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.

Keywords

2-Furylbenzimidazole; Angiogenesis; HepG2; MCF-7; VEGFR-2.

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