Abstract
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•Benzimidazole substituted oxindolinone hybrids as VEGFR-2 and EGFR inhibitors.•The IC50 value of 5b was found 6.81 and 13 nM against VEGFR-2 and EGFR, respectively.•The cytotoxicity was found as GI50 at 0.9 µM against epidermoid carcinoma cells.•Mechanistically 5b governs through VEGF/EGF, p53, bcl/bax and MMP9 signalling proteins.•Comparatively 5b was found more potent and safer than other dual inhibitors.•The dual inhibition was facilitated due to conformational switch in designed molecules.
Dual TK inhibitors have shown significant clinical effects against many tumors, but with unmanageable side effects. Design approach and selectivity of these inhibitors plays substantial role in their potency and side-effects. Understanding the homology of binding sites in targeted receptors, and involvement of signaling proteins after the inhibition might help in producing less toxic but effective inhibitors. Herein, we designed benzylideneindolon-2-one derivatives based on homology modeling in binding sites of VEGFR-2 and EGFR receptors as dual- inhibitor potent anticancer compounds with high selectivity. The benzylideneindolon-2-one derivatives were found to possess conformational switch in form of oxindole, substituted at 2-benzimidazole. Within synthesized compounds, 5b was found most active in in-vitro enzyme inhibition assay against VEGFR-2 and EGFR with highest IC50 value of 6.81 ± 2.55 and 13.04 ± 4.07 nM, respectively. Interestingly, cytotoxicity studies revealed selective toxicity of compound 5b against proliferation of A-431 cell lines (over expressed VEGFR-2 and EGFR) with GI50 value of 0.9 ± 0.66 µM. However, the compounds showed mild to moderate activity in all other cancer cell line in the range of 0.2–100 μM. Further mode of action studies by flow cytometry and western blot on A-431 indicated that they work via apoptosis at S- phase following Bcl/Bax pathway, and cell migration via MMP9. 5b not only suppressed tumor growth but also improved vandetanib associated with weight loss toxicity. Moreover, 5b was found safer than sunitinib and erlotinib with LD50 of 500 mg/kg body weight. These results propose 5b as potential anti-tumor drug with safer profile of conventional inhibitors of VEGFR-2 and EGFR for solid tumors.