Design, synthesis and molecular modeling study of some new isoxazole derivatives with potential biological activity / Mohamed Gamal Mohamed Behery ; Supervised Farghaly A. Omar , Amal A. M. Eissa , Sahar M. Abouseri

Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmaceutical Chemistry

VEGFRs play a critical role in several signal transduction pathways essential for angiogenesis and cell migration. VEGFRsare a particularly attractive target because they are expressed almost exclusively in endothelial cells and are highly up regulated in many tumor endothelia types. This investigation presents the results of in vitro anticancer activity of novel twenty eight compounds includingisoxazole{u2013}based carboxamides 3(a-d); ureates 4(a-g), 5, 6, 7a,b, 8; and hydrazones 9(a-f), 10(a-d), 11a,b as potential inhibitors of VEGFR2. The anticipated carboxamides and ureates were synthesized by converting the key intermediates 5-(aryl)-isoxazole-3-carbohydrazides 1a,b to the corresponding carbonylazides 2a,b followed by treatment with the appropriate amines.The hydrazones are directly attained through condensation of the carbo-hydrazide 1a, b with selected aldehydes and/or ketones. The structures of the targeted compounds were confirmed by elemental and spectral analyses. A preliminary in vitro anti-cancer activity of the studied compounds, at a concentration of 10-5 M, on 60 cancer cell lines (NCI, USA) revealed promising growth inhibitory activity of the carboxamide 3c with mean %GI = 30.9.Explicitly, 3c showed anticancer activity against leukemia (HL-60(TB), K-562 and MOLT-4), colon cancer (KM12) and melanoma (LOX IMVI) cell lines with %GI = 73.56, 70.79, 80.79, 79.17 and 92.21, respectively. Evaluation of growth inhibitory activity of the synthesized compounds againsthepatocellular carcinoma HepG2 showed superior activity of eight compounds 4a, 4c, 8, 9d, 9e, 10a, 10c and 11a with IC50 = 3.98, 2.59, 0.84, 2.09, 2.63, 0.79, 0.69 and 3.42 nM, respectively, which is comparable or better than that of the reference drug, Sorafenib (IC50 = 3.99 nM). The results of VEGFR2 kinase inhibition assay demonstrate that, compounds 8 and 10a are the most active inhibitors with IC50 = 23.31 and 26.55 nM, respectively, (Sorafenib IC50 = 28.1nM).

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