The reaction of cyclohexan-1,3-dione (1) with ethyl orthoformate (2) in acetic acid gave the 2-(ethoxymethylene)cyclohexane-1,3-dione (3). The latter compound was used for further heterocyclization reactions to give thiophene, pyrazole and pyran derivatives. The cytotoxicity of the newly synthesized compound against the six cancer cell lines NUGC, DLDI, HA22T, HEPG2, HONE1 and MCF showed that compounds 5, 10c, 10d, 13b, 14a, 18b, 18d, 18e and 20b were the most potent compounds. On the other hand, the toxicity of these compounds against shrimp larvae indicated that compounds 7a, 10c, 13b, 14a, 18b and 18d were non toxic against the tested organisms. Inhibition of the most potent compounds towards the tyrosine kinases c-kit, FIT-3, Vascular Endothelial Growth Factor Receptor (VEGFR)-2, Estimated Glomerular Filtration Rate (EGFR) and Platelet-Derived Growth Factor Receptor (PDGFR) revealed that compounds 5, 10c, 10d, 13b, 18b, 18d, 18e and 20b were of the highest inhibitory effect. The Pim-1 kinase test revealed that compounds 10d, 18b and 20b were of the highest inhibitory effect. In addition, the c-Met enzymatic activities showed that compounds 10c, 10d, 18b, 18e, 19 and 20b showed higher potencies against c-Met kinase than the reference foretinib. On the other hand, compounds 7a, 7b, 10d, 13a, 13b, 14a, 14b, 16a, 16b, 17, 18a-f, 19 and 20 showed higher inhibition towards PC-3 cell line than the reference SGI-1776. Compounds 10c and 18b were of common potencies and their molecular docking was described.
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