Synthesis, Biological Evaluation, and Docking Studies of New 2-Furylbenzimidazoles as Anti-Angiogenic Agents: Part II

• Published in: Archiv der Pharmazie (Weinheim) 2014-04, Vol.347 (4), p.291-304
• Main Authors: Temirak, Ahmed, Shaker, Yasser M., Ragab, Fatma A. F., Ali, Mamdouh M., Soliman, Salwa M., Mortier, Jeremie, Wolber, Gerhard, Ali, Hamed I., Diwani, Hoda I. El
• Format: Article
• Language: English
• Subjects: 2-(2-Furyl)-1H-benzimidazoles; Angiogenesis; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Breast Neoplasms - blood supply; Breast Neoplasms - drug therapy; Cytotoxicity; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; Molecular Docking Simulation; Molecular modeling; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Structure-Activity Relationship; Tamoxifen - pharmacology; Vascular endothelial growth factor (VEGF); Vascular Endothelial Growth Factor A - antagonists & inhibitors
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201300356

The 2‐(5‐methyl‐2‐furyl)‐1H‐benzimidazole moiety has shown promising activity against vascular endothelial growth factor (VEGF)‐induced angiogenesis. In part I of this study, we have synthesized new analogs and tested their anti‐angiogenic potentials. Here, we continue our previous study with different new analogs. Some compounds show promising cytotoxic activity against the human breast cancer cell line MCF‐7, with IC50 in the range of 7.80–13.90 µg/mL, and exhibited remarkable in vitro inhibition against VEGF in the MCF‐7 cancer cell line, with 95–98% of inhibition in comparison to tamoxifen as reference (IC50: 8.00 µg/mL, % of inhibition = 98%). Additionally, a molecular docking study was carried out to gain insight into plausible binding modes and to understand the structure–activity relationships of the synthesized compounds. Newly synthesized 2‐furylbenzimidazoles inhibited the VEGF with %inhibition of 95–98% and showed cytotoxic activity against the MCF‐7 breast cancer cell line (IC50: 7.80–13.90 µg/mL). Compound 6k is highly stabilized in the binding site of VEGFR2 (PDB: 3EWH), with two hydrogen bonds with ASP1046 and GLU885 in addition to the hydrophobic interactions in sub‐sites I, III, and the furyl binding site.