Molecular Design, Synthesis And Anticoagulant Activity Research Of Novel Fluorinated Dabigatran Derivatives

The main content of this paper is to combine the benefits of dabigatran and fluorine atom during anticoagulant treatment. Using Surflex-Dock module of the computer-aided design software SYBYL-X 2.0 and thrombin protein (PDB:1 KTS) as receptors for computer-aided simulation and molecular docking of dabigatran derivatives. Fluorine atoms were introduced into direct thrombin inhibitor of dabigatran. Then the structure of dabigatran was modified to design a series of novel fluorinated dabigatran derivatives.15 compounds, which scores were high, were screened by computer simulation of scoring system. Finally, we synthesized 15 fluorinated dabigatran derivatives via Michael addition reaction; carboxylic acylating reaction, nitro reduction reaction, condensation closed-loop response, Pinner reaction and hydrolysis reaction.Through the screening of the inhibition ratio of these compounds,11 derivatives were chosen to for anticoagulant activities test in vitro. The test results show that all compounds exhibited stable and moderate anticoagulant activities. Wherein the compounds 15f,15k,15n and 15o compared with the positive control medicine dabigatran (IC50= 1.23 nmol/L), showed equivalent anticoagulant activity, with IC50 values of 1.81,3.21,3.69 and 2.16 nmol/L, respectively. Furthermore, we selected compounds 15k and 15o to test the anticoagulant activity index in vivo--impact on the formation of SD rat arterial-venous thrombosis. In the detection of the two subjects, all could effectively inhibit the embolus weight of arterial-venous thrombosis, which was comparable with that of the positive control medicine dabigatran, respectively with inhibition ratio of (76.23+3.68)% and (84.66+0.56)%. Above all, the compounds could be as candidates of anticoagulant drugs for further research.