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Design, synthesis, and antitumor evaluation of new pyridazinone scaffolds as dual EGFR/VEGFR-2 kinase inhibitors and apoptotic cells inducers.

Sara Y. Ewieda,Eman M Ahmed,Nirvana A. Gohar,Shaymaa G. Ibrahim,Marwa A Essa,M. T. Nemr

Published 2025 in Bioorganic chemistry (Print)

ABSTRACT

Three new sets of pyridazinone 5a-h, 6a,b, and 7a,b were designed and synthesized as potent antineoplastic agents against colon (HCT116), liver (HepG2), and breast (MCF-7) cancer cell lines. Compounds 5b,f and 7a displayed excellent cytotoxic activity against all tested cell lines, HCT116, HepG2 and MCF-7 with IC50 values ranging from 7.69-15.66, 9.46-26.44 and 6.93-18.40 μM, respectively, compared to doxorubicin (IC50 = 5.23, 4.5 and 4.17 μM), sorafenib (IC50 = 5.47, 9.18 and 7.26 μM) and erlotinib (IC50 of 5.61, 18.12 and 48.36 μM) respectively. Furthermore, the safety of the synthesized derivatives was assessed on the normal breast epithelial cell line (MCF10A). The most potent derivatives 5b,f, and 7a exhibited notable selectivity toward cancer cells (SI values of 2.29-12.77) compared to erlotinib (SI values of 0.56-4.84). In addition, the most potent derivatives 5b,f, and 7a were tested for their affinity to kinases, and it was ranging from 33 % to 60 %. Further assessment of these most potent derivatives against EGFR/VEGFR-2 kinase inhibition revealed that, pyridazinone 5f had superior EGFR kinase inhibitory activity (IC50 = 0.042 μM) compared to Erlotinib (IC50 = 0.076 μM). Furthermore, compounds 5b and 7a showed potent EGFR kinase inhibitory activity (IC50 = 0.095 and 0.191 μM, respectively). Moreover, compounds 5b and 5f had outstanding VEGFR-2 kinase inhibitory activity (IC50 = 0.051 and 0.032 μM, respectively), surpassing Sorafenib (IC50 = 0.056 μM). In addition, compound 7a exhibited advanced VEGFR-2 kinase inhibitory activity (IC50 = 0.090 μM). Additionally, flow cytometric analysis revealed that the most potent derivative 5f induces cell cycle arrest at the G1 phase, leading to inhibition of cell proliferation and the induction of apoptosis. Molecular docking studies of compounds 5b,f, and 7a showed strong binding affinities to the active sites of the kinases, similar to those of Erlotinib and Sorafenib, which accounts for their high potency. The physicochemical and ADME properties of the most effective pyridazinone derivative, 5f, were investigated using SwissADME. The abovementioned findings suggest that compound 5f is a promising lead for the possible design of dual EGFR/VEGFR-2 kinase inhibitors.

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