Design,Synthesis And Biological Activity Of FXa Inhibitors With O-aminobenzoic Acid As Scaffold

Factor Xa plays a key role in the coagulation system and has become a promising target for anticoagulation.In this thesis,the role of FXa in the process of thrombosis,its binding methods with FXa inhibitors and research progress of different typical FXa inhibitors in recent years were introduced in detail.On this basis,we focus on the design,synthesis and anticoagulant activity of compounds with 1,2-substituted benzene ring.Darexaban was taken as the lead compound and the structural characteristics of Rivaroxaban and its combination with target sites were also studied.By studying and summarizing the reports of different typical FXa inhibitors,their structure characteristics and the binding methods of the target with them was analyzed.A series of compounds with 1,3-substituted benzene ring and o-aminobenzoic acid as scaffold were designed.Based on the results of the activity test,compounds with o-aminobenzoic acid as scaffold were selected for the next development.After that,P1,P4 and the substituents on the benzene ring of the target compounds were investigated respectively.Sixteen new compounds with 1,3-substituted benzene ring as scaffold and fifty-nine new compounds with o-aminobenzoic acid as scaffold were designed and synthesized.None of the synthesized compounds were reported in the literature and their chemical structures were confirmed by MS or HRMS and 1H NMR spectrometry.The synthetic process of Rivaroxaban,a positive drug,was studied and optimized.The total yield was 36.3%and the final product purity was 99.6%.And three major impurities produced by the process were synthesized.The synthesis process of the key intermediate 1-(4-aminophenyl)pyridin-2(1H)-one in the synthesis of the target compounds(Ullmann coupling reaction)was optimized and improved to obtain a better yield and purity.At the same time,the reduction and acylation reactions used for the synthesis of target compounds of different structure types were respectively optimized and improved.The inhibitory activity of factor Xa in vitro,the prothrombin time and the inhibitory activity of factor Ⅱa in vitro were used for screening the target compounds’ anticoagulant activity.Five target compounds B2,C2,C6,C9 and C13 showed good anticoagulant activity,and some of the activity test results even outperformed the positive drug Darexaban.This has the value of further research.The target compounds B2,C9 and C13,which showed good anticoagulant activity and have certain structural characteristics,were subjected to docking simulation studies to analyze the binding mode of the compounds at the active site of FXa.The structure-activity relationship of the target compounds were discussed primarily,which lays a theoretical foundation for further research.