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

Abstract

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).

Keywords:

• Cytotoxic activity
• heterocyclic compounds
• hydrazonoyl chlorides
• pyrimidinone
• thioglycolic acid

Acknowledgments

The authors thanks College of Science and pharmacy, Jouf University, Sakaka, Kingdom of Saudi and Chemistry Department, Faculty of Science, Zagazig University, Zagazig, for helping to bring out this research. A.F. El-Farargy thanks Prof. Dr. N. Krausa, Lehrstuhl für Organische Chemie, TU Dortmund, Germany, for his continuous help and repeated invitation.

Disclosure statement

The authors declare that they have no conflict of interest.