Novel Aryl‐Modified Benzoylamino‐N‐(5,6‐dimethoxy‐1H‐benzoimidazol‐2‐yl)‐heteroamides as Potent Inhibitors of Vascular Endothelial Growth Factor Receptors 1 and 2

Abstract

Tumor angiogenesis has become an important target for antitumor therapy, with most current therapies aimed at blocking the vascular endothelial growth factor (VEGF) pathway. The VEGF and its receptors have been implicated as key factors in tumor angiogenesis and are major targets in cancer therapy. A series of aryl‐modified benzoylamino‐N‐(5,6‐dimethoxy‐1H‐benzoimidazol‐2‐yl)‐heteroamides were synthesized from 2‐amino‐5,6‐dimethoxy benzimidazole and aryl‐substituted benzoylamino hetero acids. The new compounds were tested for inhibition of VEGF receptors I and II (VEGFR‐1 and VEGFR‐2). Compound 6e displayed VEGFR‐2 inhibitory activity with a 50% inhibition concentration value as low as 0.020 μM in a homogeneous time‐resolved fluorescence enzymatic assay. VEGFR‐2 active compounds display good activity against VEGFR‐1 as well.

The medicinal panorama of benzimidazoles and their scaffolds as anticancer and antithrombotic agents: A review

“…Single et al [66] in the year 2016 synthesized an array of novel pyrazolo [3,4-d] Abhishek Ashok and his colleagues [67] in the year 2016 designed and synthesized a sequence of aryl-modified substituted benzimidazole hetero amides 100(a-h) from 98 and 99(a-b) outlined in Using microwave irradiation in 2016, Bui and his colleagues [68] produced 12 novel arrays of the 2-substituted quinolizinylbenzimidazoles 104(a-f) and 2-substituted naphthalyl-benzimidazoles 107(a-f) derivatives, which are shown in Scheme 14. By using tamoxifen as the reference compound in the MTT experiment, all the generated substances were assayed for their in vitro cytotoxic activities against the MCF-7 cancer cell lines.…”

“…Abhishek Ashok and his colleagues [ 67 ] in the year 2016 designed and synthesized a sequence of aryl‐modified substituted benzimidazole hetero amides 100(a–h) from 98 and 99(a–b) outlined in Scheme 13. Vascular endothelial growth factor factor (VEGFR) tyrosine kinase inhibition of all the derivatives was estimated by evaluating the phosphorylation level of the poly‐glu–ala–tyr‐biotin peptide by the homogeneous time‐resolved fluorescence (HTRF) method, and vandetanib was used as a standard (IC 50 = 45 ± 15 nM).…”

Versatile mechanisms of 2-substituted benzimidazoles in targeted cancer therapy

“…VEGFR-2 active compounds display good activity against VEGFR-1 up to 91% inhibition at 10 μM concentration. The compounds likewise give a chance of establishing the framework for promising molecules of anticancer activity [94].…”

Design, Synthesis, and Molecular Modeling Studies of a Novel Benzimidazole as an Aromatase Inhibitor

“…The ring structure is also an isostere of DNA bases that carry purine and pyrimidine cores, and it can as well be a purine antimetabolite . It has been proven by various studies that benzimidazole derivatives with anticancer activity show their activities by different mechanisms through DNA intercalation, topoisomerase I and II inhibition, an androgen receptor antagonistic effect, PARP-poly inhibition, dihydro-folate reductase (DHFR), aromatase inhibition, and microtubule inhibition. − Various classes of therapeutically active benzimidazole derivatives are available in the market such as bendamustine, veliparp, carbendazim, and nocodazole.…”