Novel uracil derivatives depicted potential anticancer agents: In Vitro, molecular docking, and ADME study

Abstract

Using a simple technique to prepare many uracil derivatives as Schiff base of uracil 4, bis 6-amino[5-(1-(4-aryl)ethylidene)amino)]pyrimidine-2,4-dione 5–12 by heating of 5,6-diamino-1-substituteduracils 1a-e in few drops of DMF with acetophenones by light torch flame and imidazolopyrimidine-2,4-dione 13 which prepared from 5,6-diaminouracil hydrochloride 3a by heating under reflux with 4-bromoacetophenone. Moreover, 6-cyano-7-ethoxypyridopyrimidines 14–16 were prepared by refluxing of 6-amino-1-(2-chlorobenzyl)uracil 1d with ethyl benzylidene cyanoacetate in TEA through conjugate addition followed by intramolecular heterocyclization. All novel synthesized compounds were evaluated for their anticancer activity against three kinds of cancer including liver cancer (HepG2, and Huh7) cell lines, breast cancer (MCF7) cell line, and lung cancer (A549) cell line. Moreover, toxicity of the most cytotoxic compound was evaluated against normal cells (MDCK). Compounds 6, 7, 15, and 16 were the best cytotoxic compounds against most of treated cancer cell lines, and most interestingly they had no toxicity against normal cells. Furthermore, Compound 7 had high binding affinity with cyclin dependent kinase 2 (CDK2), with ability to induce apoptosis in lung cancer cells. Further investigations are needed to elaborate with these novel synthesized compounds with potential cytotoxic activity to develop new effective chemotherapy.