title: Novel dabigatran derivatives with a fluorine atom at the C-2 position of the terminal benzene ring: Design, synthesis and anticoagulant activity evaluation.
abstract: This manuscript describes the preparation of dabigatran derivatives and their inhibitory potentials toward human thrombin. Among the tested compounds, 7c, 7k, 7m and 7o, with IC50values of 1.54, 0.84, 1.18 and 1.42 nM, exhibited comparable inhibitory activity to dabigatran (IC50= 1.20 nM). The in vivo anti-thrombotic activity of compounds 7c and 7o in SD rats was studied. Results showed that intravenously administering the two compounds significantly inhibited the growth of thrombus with an inhibition rate of (84.24 ± 1.53)% and (84.57 ± 0.45)%, which were comparable to that of dabigatran (85.07 ± 0.61)%. Furthermore, the docking simulation of active compounds (7k and 7m) provided a potential binding model. Results indicated that these compounds could be further investigated to determine their anticoagulant activities.
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Yang
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Gao
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China. Electronic address: clab@sit.edu.cn.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Ren
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001554:Benzene / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D000069604:Dabigatran / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000991:Antithrombins; D005461:Fluorine; D013917:Thrombin; D000069604:Dabigatran; D001554:Benzene
keywords: Anticoagulant activity; Fluorinated dabigatran derivatives; Molecular docking; Synthesis