title: Molecular design, synthesis and anticoagulant activity evaluation of fluorinated dabigatran analogues.
abstract: In the present study, a series of unreported fluorinated dabigatran analogues, which were based on the structural scaffold of dabigatran, were designed by computer-aided simulation. Fifteen fluorinated dabigatran analogues were screened and synthesized. All target compounds were characterized by (1)H NMR, (13)C NMR, (19)F NMR and HRMS. According to the preliminary screening results of inhibition ratio, eleven analogues (inhibition ratio >90%) were evaluated for antithrombin activity in vitro (IC50). The test results expressed that all the analogues showed effective inhibitory activities against thrombin. Especially, compounds 8f, 8k and 8o, with IC50 values of 1.81, 3.21 and 2.16nM, respectively, showed remarkable anticoagulant activities which were in the range of reference drug dabigatran (IC50=1.23nM). Moreover, compounds 8k and 8o were developed to investigate their anticoagulant activities in vivo. In those part, compound 8o exhibited a fairly strong inhibitory action for arteriovenous thrombosis with inhibition ratio of 84.66%, which was comparable with that of dabigatran (85.07%). Docking simulations demonstrated that these compounds could act as candidates for further development of novel anticoagulant drugs.
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. Electronic address: clab@sit.edu.cn.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Ren
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Dong
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000069604:Dabigatran / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D054879:Halogenation; D006801:Humans; D062105:Molecular Docking Simulation; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy*
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D013917:Thrombin; D000069604:Dabigatran
keywords: Anticoagulant activity; Fluorinated dabigatran analogues; Molecular design; Synthesis