Design and synthesis of new 2-substituted benzimidazoles as dual inhibitor for c-Met and VEGFR-2

Hanan M Refaat; Heba A Ibrahim; Kamilia Amin; Fadi Awadallah

doi:10.4172/2167-7689-C1-025

Design and synthesis of new 2-substituted benzimidazoles as dual inhibitor for c-Met and VEGFR-2

9^th Annual European Pharma Congress

June 26-28, 2017 Madrid, Spain

Hanan M Refaat, Heba A Ibrahim, Kamilia Amin and Fadi Awadallah

Future University in Egypt, Egypt
Cairo University, Egypt

Posters & Accepted Abstracts: Pharmaceut Reg Affairs

Abstract :

C-Met (a receptor tyrosine kinase) has been shown to collaborate synergistically with VEGFR-2 (a member of vascular endothelial growth factor receptors belonging also to tyrosine kinase), resulting in promoting development of angiogenesis and progression of various human cancers. In recent years, some c-Met/VEGFR-2 dual inhibitors have been reported or have entered clinical trials. For example Treanda (bendamustine hydrochloride) comprises a benzimidazole ring with a butyric acid substituent and was approved by FDA for the treatment of chronic lymphotic leukemia. The rational design of target molecules was based on its in silico molecular docking study and in silico ADMET study to provide an insight about the binding mode into binding sites of both c-Met/VEGFR-2 as a dual inhibitor. Thus, the benzimidazole ring of bendamustine was retained, buturic acid was replaced by nitro group and the bis-(chloroethyl) amine group (mechlorethamine) was substituted with several biologically active scaffolds such as oxadiazole, thiadiazole, and triazolo-thiadiazines. Five series (5a-b, 7aâ�?�?o, 10a-d, 13aâ�?�?b and 15aâ�?�?c) of 2- substituted benzimidazole derivatives were synthesized via condensation of 4-nitro-o-phenylenediamine with �?±-ketoglutaric acid. The cytotoxic activities of some of the designed analogues were carried out at the National Cancer Institute (NCI), USA; at a single dose (10 �?¼M), against full NCI 60 human cell lines. Most of the tested compounds, 5b (793196/1), 7i (793197/1), 13a (793191/1), 13f (793193/1), 13i (793192/1), 15a (793199/1) and 15b (793200/1) exhibited significant anti-proliferative activity. Further, all of the prepared compounds are under enzymatic screening for their inhibitory activity for both c-Met and VEGFR-2 as dual inhibitor.