Activated cyanoacetamide in heterocyclic synthesis: Design, synthesis, antitumor activity and docking study of some new pyrimidine derivatives

Abstract

The precursor cyanoacetamide derivatives (6) were achieved by the reaction of pyrimidine derivative 5 with cyanoacetic acid catalyzed by acetic anhydride. The reaction of cyanoacetamide derivative 6 with different reagents afforded many heterocyclic systems such as thioacetic acid (9), dithiolane derivatives (11) and (12), 1,8-naphthyridine (14), quinoline derivatives (17) and (18), pyridine derivatives 20, 22, 24, 26, and 27, pyridazine (30), pyranopyrimidine (32), and pyrazolopyrimidine (34). All the newly synthesized compounds were characterized with spectroscopic analyses. Compounds were tested for their anticancer activity against three human cancer cell lines: hepatocellular carcinoma (HepG-2), colon cancer (HCT-116), and mammary gland breast cancer (MCF-7). The studied compound's cytotoxic activity ranged from very strong to very weak. The most active compounds were 9, 10, 11, 27, and 34. The binding disposition of the docked compounds, in particular 9, 10, 11, 27, and 34, towards the binding site of AKT complexed with co-crystallized ligand was investigated using molecular docking (PDB = 4EJN).