Ewieda Sara Y, Ahmed Eman M, Gohar Nirvana A, Ibrahim Shaymaa G, Essa Marwa A, Nemr Mohamed T M
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, 11562 Cairo, Egypt.
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street, 11562 Cairo, Egypt.
Bioorg Chem. 2025 Nov;166:109157. doi: 10.1016/j.bioorg.2025.109157. Epub 2025 Oct 26.
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 IC values ranging from 7.69-15.66, 9.46-26.44 and 6.93-18.40 μM, respectively, compared to doxorubicin (IC = 5.23, 4.5 and 4.17 μM), sorafenib (IC = 5.47, 9.18 and 7.26 μM) and erlotinib (IC 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 (IC = 0.042 μM) compared to Erlotinib (IC = 0.076 μM). Furthermore, compounds 5b and 7a showed potent EGFR kinase inhibitory activity (IC = 0.095 and 0.191 μM, respectively). Moreover, compounds 5b and 5f had outstanding VEGFR-2 kinase inhibitory activity (IC = 0.051 and 0.032 μM, respectively), surpassing Sorafenib (IC = 0.056 μM). In addition, compound 7a exhibited advanced VEGFR-2 kinase inhibitory activity (IC = 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.
设计并合成了三组新型哒嗪酮5a-h、6a,b和7a,b，作为针对结肠（HCT116）、肝脏（HepG2）和乳腺（MCF-7）癌细胞系的强效抗肿瘤药物。化合物5b,f和7a对所有测试细胞系HCT116、HepG2和MCF-7均表现出优异的细胞毒性活性，其IC值分别为7.69 - 15.66、9.46 - 26.44和6.93 - 18.40 μM，相比之下，多柔比星（IC = 5.23、4.5和4.17 μM）、索拉非尼（IC = 5.47、9.18和7.26 μM）和厄洛替尼（IC分别为5.61、18.12和48.36 μM）。此外，在正常乳腺上皮细胞系（MCF10A）上评估了合成衍生物的安全性。与厄洛替尼（SI值为0.56 - 4.84）相比，最有效的衍生物5b,f和7a对癌细胞表现出显著的选择性（SI值为2.29 - 12.77）。此外，测试了最有效的衍生物5b,f和7a对激酶的亲和力，其范围为33%至60%。对这些最有效的衍生物针对EGFR/VEGFR-2激酶抑制的进一步评估表明，哒嗪酮5f具有优于厄洛替尼（IC = 0.076 μM）的EGFR激酶抑制活性（IC = 0.042 μM）。此外，化合物5b和7a显示出强效的EGFR激酶抑制活性（IC分别为0.095和0.191 μM）。此外，化合物5b和5f具有出色的VEGFR-2激酶抑制活性（IC分别为0.051和0.032 μM），超过索拉非尼（IC = 0.056 μM）。此外，化合物7a表现出先进的VEGFR-2激酶抑制活性（IC = 0.090 μM）。此外，流式细胞术分析表明，最有效的衍生物5f诱导细胞周期停滞在G1期，导致细胞增殖抑制和凋亡诱导。化合物5b,f和7a的分子对接研究表明，它们与激酶的活性位点具有很强的结合亲和力，类似于厄洛替尼和索拉非尼，这解释了它们的高效性。使用SwissADME研究了最有效的哒嗪酮衍生物5f的理化性质和ADME性质。上述发现表明，化合物5f是设计双EGFR/VEGFR-2激酶抑制剂的有前景的先导化合物。
