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Benzimidazole-Based VEGFR-2 Inhibitors Inspired by Sorafenib: Synthesis, Biological Evaluation, and Mechanistic
Mohamed Atia Dewidar1,2, Heba Abdelrasheed Allam3, Hatem A Abdel-Aziz4
1Postgraduate Program in Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Abstract:
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a central role in tumor angiogenesis and remains a well-established therapeutic target in cancer treatment. In this study, twenty-six benzimidazole-based derivatives (3a-k, 5a-d, 8a-g, and 10a-d) were rationally designed to incorporate the essential structural and pharmacophoric features required for effective VEGFR-2 inhibition, followed by their synthesis and biological evaluation. In vitro kinase assays demonstrated that the synthesized derivatives inhibited VEGFR-2 with IC50 values ranging from 0.061 to 1.895 µM. Based on their enzymatic potency, the most active compounds (3f, 3h, 3j, 8d, and 8g) were further investigated for antiproliferative activity against HUVEC, MCF-7, and HepG2 cell lines. Among them, Compound 3f exhibited IC50 values of 13.34, 5.32, and 5.02 µM, respectively, showing activity comparable to sorafenib. Evaluation against normal MCF-10A and Vero cell lines indicated favorable biocompatibility and a reasonable selectivity profile. Mechanistic studies revealed that 3f induced G2/M-phase arrest, promoted apoptosis, and suppressed cell migration, accompanied by a reduction in VEGFR-2 protein expression levels. Molecular docking suggested that the synthesized derivatives adopt a binding mode consistent with Type II VEGFR-2 inhibitors, while in silico ADME and toxicity predictions supported an acceptable toxicity profile and drug-like characteristics.
Insights
Researchers designed and synthesized novel benzimidazole derivatives targeting vascular endothelial growth factor receptor-2 (VEGFR-2) for cancer therapy. Compound 3f demonstrated potent VEGFR-2 inhibition and significant antiproliferative effects, showing promise as a new cancer therapeutic agent.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Oncology
Background:
- Vascular endothelial growth factor receptor-2 (VEGFR-2) is crucial for tumor angiogenesis and a key therapeutic target in cancer.
- Targeting VEGFR-2 offers a promising strategy for developing novel anti-cancer drugs.
Purpose of the Study:
- To design, synthesize, and evaluate novel benzimidazole-based derivatives as potent inhibitors of VEGFR-2.
- To investigate the antiproliferative activity and mechanism of action of the most promising compounds.
Main Methods:
- Rational design and synthesis of 26 benzimidazole derivatives.
- In vitro kinase assays for VEGFR-2 inhibition.
- Antiproliferative assays against cancer cell lines (HUVEC, MCF-7, HepG2) and normal cell lines (MCF-10A, Vero).
- Mechanistic studies including cell cycle analysis, apoptosis induction, and migration assays.
- Molecular docking and in silico ADME/toxicity predictions.
Main Results:
- Synthesized derivatives inhibited VEGFR-2 with IC50 values ranging from 0.061 to 1.895 µM.
- Compound 3f showed potent antiproliferative activity (IC50: 13.34 µM in HUVEC, 5.32 µM in MCF-7, 5.02 µM in HepG2), comparable to sorafenib.
- Compound 3f demonstrated favorable biocompatibility and selectivity, induced G2/M-phase arrest, promoted apoptosis, suppressed migration, and reduced VEGFR-2 expression.
- Molecular docking indicated a Type II inhibition mode, and in silico predictions supported favorable drug-like properties and toxicity profiles.
Conclusions:
- Novel benzimidazole derivatives effectively inhibit VEGFR-2 kinase activity.
- Compound 3f exhibits significant anti-cancer potential through multiple mechanisms, including cell cycle arrest and apoptosis induction.
- These findings support the development of benzimidazole derivatives as potential therapeutic agents for cancer treatment targeting VEGFR-2.
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