Abstract
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•Two series of pyrazole- and pyrimidine- based dual EGFR/VEGFR-2 inhibitors (24 compounds) were designed and synthesized.•The anti-proliferative activities were examined against five selected cancer cell lines.•The most active candidates were evaluated against both EGFR and VEGFR-2 enzymes.•Cell cycle analysis and Annexin V-based flow cytometry in the HepG-2 cell line were performed.•Two molecular docking studies, ADMET, and toxicity in silico studies were carried out.•A very promising structure–activity relationship (SAR) was concluded.
Guided by the pharmacophoric features of both EGFR and VEGFR-2 antagonists, two novel series of 4-methoxyphenyl pyrazole and pyrimidine derivatives [(4a-c) and (5a-c, 6, 7a-c, 8, 9, 10, 11a,c, 12, 13a-c, 14a-c, and 15a,b)], respectively, were designed and synthesized as dual EGFR/VEGFR-2 inhibitors. Interestingly, compound 12 showed very strong antiproliferative effects towards all the five studied cell lines (HepG-2, MCF-7, MDA-231, HCT-116, and Caco-2) with IC50 values of 3.74, 7.81, 4.85, 2.96, and 9.27 µM, respectively. Also, it achieved the highest inhibitory activities against both EGFR and VEGFR-2 as well (IC50 = 0.071 and 0.098 µM) compared to the two reference drugs, erlotinib (IC50 = 0.063 µM) and sorafenib (IC50 = 0.041 µM), respectively. Moreover, four compounds (4a, 7a, 7c, and 12) were selected for further evaluation through cell cycle analysis and Annexin V-based flow cytometry assay in the HepG-2 cell line. In addition, deep computational studies including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions were performed for the designed compounds to evaluate the prospective drug candidates. Finally, analyzing the structure–activity relationship (SAR) of the new derivatives gives us a lot of interesting promising results which could help medicinal chemists to design more potent drug candidates soon as well.