Design, Synthesis, Molecular Docking of Novel Substituted Pyrimidinone Derivatives as Anticancer Agents

• Published in: Polycyclic aromatic compounds Vol. 42; no. 5; pp. 2538 - 2554
• Main Authors: Ghoneim, Amira Atef, El-Farargy, Ahmed Foud, Bakr, Rania B.
• Format: Journal Article
• Language: English
• Published: Philadelphia Taylor & Francis 28-05-2022; Taylor & Francis Ltd
• Subjects: Adenocarcinoma; Anticancer properties; Antitumor activity; Antitumor agents; Cancer; Chemical synthesis; Chlorides; Colorectal carcinoma; Cytotoxic activity; Cytotoxicity; Epidermal growth factor receptors; Heterocyclic compounds; hydrazonoyl chlorides; Iodides; Methylation; Molecular docking; Phosphorus; Phosphorus pentoxide; Prostate; Pyrazole; Pyrazoles; pyrimidinone; Sodium hydroxide; Thiadiazoles; Thioglycolic acid; Tumor cell lines
• ISSN: 1040-6638; 1563-5333
• DOI: 10.1080/10406638.2020.1837888

Novel derivatives of pyrimidinone ring carrying some five-membered heterocycles had been designed and prepared. 1,3-Thiazolidin-4-one derivative 7 was prepared by the reaction of 1,2,3,4-tetrahydro-4-(4-hydroxyphenyl)-6-methyl-N′-((naphthalen-4-yl)methylene)-2-oxopyrimidine-5-carbohydrazide 6 with thioglycolic acid. Reacting the hydrazide 5 with benzoyl chloride gave compound 8 which cyclized to 1,3,4-oxadiazole 9 by the use of phosphorus pentoxide. Moreover, the pyrazole derivative 10 was obtained from reacting compound 5 with ethyl acetoacetate. Furthermore, the reaction of the hydrazide 5 with phenyl isothiocyanates produced the carbothioamide 11 which refluxed with hydrazonoyl chloride to yield 1,3,4-thiadiazole derivative 14. In addition, 1, 2,4-triazole derivative 16 was prepared via reacting the carbothioamide 11 with sodium hydroxide followed by methylation with methyl iodide. The structures of the newly prepared heterocyclic compounds were determined by spectral and elemental analysis. The cytotoxic activity of the target compounds (7, 9, 10, 14, and 16) were estimated in vitro against PC-3 (prostate adenocarcinoma), human HepG-2 (liver carcinoma), and HCT116 (colorectal carcinoma) cell lines using MTT assay. All the tested compounds appeared high level of inhibition against PC-3 and HCT116 cell lines, while appeared weak inhibitory action against HepG-2 cell lines, especially, the thiadiazole derivative 14. Furthermore, docking study had been carried out on the targets 7, 9, 10, 14, and 16 within EGFR as a prediction for the anticancer activity. All the docked compounds showed good fitting with EGFR recording docking scores range (-27.99 to -19.01).