Design, Synthesis And Qsar Study Of Quinazoline-Pyrimidinedione Derivatives

Thymidylate synthase plays an essential role in the synthesis of DNA. Inhibition of TS can inhibit the biosynthesis of DNA, then, inhibit tumor cell proliferation and growth. Consequently, TS is a hot target in cancer chemotherapy, Inhibitor of TS is an important direction of anticancer research. The objective of this research is to design and synthesize of novel thymidylate synthase inhibitors. Achievement of this research is as follows:1 Three dimensional quantitative structure-activity relationships of a series of five-membered heterocyclopyrimidines derivatives as thymidylate synthase inhibitors was studied with comparative molecular field analysis (CoMFA) techniques and comparative similarity indices analysis (CoMSIA) techniques. The results provide a theoretical base for the further study of the thymidylate synthase inhibitor.2 Based on the thymidylate synthase inhibitor reported by the references, the paper used the catalytic reaction mechanism to design a series of quinazoline- pyrimidinedione derivatives with synthetic feasibility. The virtual compound library was established. The molecular docking and drug-likeness analysis were carried out. The moleculars which chould be the lead compound were screened out.3 The synthetic route to the designed quinazoline-pyrimidinedione derivative 123 was explored, The total synthesis of 2-amino-6-methylbenzoic acid, the key intermediates for the synthesis of 123, was completed from m-methylaniline via 6 steps such as aldol condensation, salt formation, hydrolysis, condensation, cyclization and oxidative ring cleavage Reaction. The synthesis process and the yield of every step were improved, and compounds were confirmed by 1HNMR.