Discovery of Novel Benzimidazoles as Potent Inhibitors of TIE-2 and VEGFR-2 Tyrosine Kinase Receptors

Abstract

We herein disclose a novel chemical series of benzimidazole-ureas as inhibitors of VEGFR-2 and TIE-2 kinase receptors, both of which are implicated in angiogenesis. Structure-activity relationship (SAR) studies elucidated a critical role for the N1 nitrogen of both the benzimidazole (segment E) and urea (segment B) moieties. The SAR results were also supported by the X-ray crystallographic elucidation of the role of the N1 nitrogen and the urea moiety when the benzimidazole-urea compounds were bound to the VEGFR-2 enzyme. The left side phenyl ring (segment A) occupies the backpocket where a 3-hydrophobic substituent was favored for TIE-2 activity.

Synthesis and biological evaluation of phthalimide dithiocarbamate and dithioate derivatives as anti-proliferative and anti-angiogenic agents-I

“…Molecular docking investigated the affinity of the designed compounds into the active site of VEGFR enzyme (PDP: 2OH4) [34]. Both the binding modes and the docking scores of the designed target compounds compared to the lead compound were evaluated.…”

New antihyperglycemic, α-glucosidase inhibitory, and cytotoxic derivatives of benzimidazoles

“…PdCl 2 (CH 3 CN) 2 is considered an important catalyst among all palladium catalysts. We carried out the synthesis of benzimidazoles by the condensation of o-phenylenediamine and substituted o-phenylenediamines (1a-h, 1 mmol) with aryl and heteroaryl carbonyl compounds (2a-h, 1 mmol) in the presence of a catalytic amount of PdCl 2 (CH 3 CN) 2 in anhydrous methanol at room temperature 27 . The mode of reaction is the formation of a Schiff base ( 1 H NMR,  8.45 singlet, 1H), followed by intramolecular cyclization resulting in benzimidazoles (3a-h; Scheme 1 and Table 1) Inhibition of glycosidases has recently become important not only due to their interesting role in delineating enzyme mechanisms and the control of postprandial hyperglycemic excursion in diabetes mellitus, but also in development of newer therapeutics targeted at, for example, cancer, viral infections including human immunodeficiency virus (HIV) and influenza, and lysosomal storage diseases, with a number of drugs in current clinical use 29 .…”

“…Therefore, the search for agents that mitigate postprandial hyperglycemia and possess cytotoxic activity against colon cancer cell lines may offer an opportunity for the development of novel therapeutics for diabetic patients. In this communication we report the synthesis of various benzimidazoles 3a-h by the condensation of ophenylenediamines (1a-h) with aromatic and heteroaromatic carbonyl compounds (2a-h) in the presence of a catalytic amount of PdCl 2 (CH 3 CN) 2 in dry MeOH at room temperature. Compounds 3a-h were evaluated for their in vitro -glucosidase inhibitory activity and cytotoxic activity on colon carcinoma line HT-29, as well as antihyperglycemic property in starch-induced postprandial hyperglycemia in rats.…”

Synthesis and Pharmacologic Evaluation of Some Benzimidazole Acetohydrazide Derivatives as EGFR Inhibitors

“…4 It is known that compounds used as inhibitors of tyrosine kinase such as sunitinib carry benzimidazole isostere indole rings, and pazopanib and axitinib have indazole rings. Furthermore, by determining that benzimidazoles exhibit protein kinase inhibitor activity [6][7][8][9] , in addition to their different biologic activities, the compounds planned to be synthesized in this study are thought to be inhibitory on the EGFR receptor, which is now known to be directly related to cancer development.…”