期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 24, 期 12, 页码 2739-2753出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.04.038
关键词
Molecular design; Synthesis; Anticoagulant activity; Fluorinated dabigatran analogues
资金
- Chemical Engineering and Technology (Perfume and Aroma Technology) plateau discipline of Shanghai Municipality
- 'Industry-University-Research Institutions' collaborative innovation fund of Shanghai Institute of Technology [XTCX2015-14]
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 H-1 NMR, C-13 NMR, F-19 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 2.16 nM, respectively, showed remarkable anticoagulant activities which were in the range of reference drug dabigatran (IC50 = 1.23 nM). 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. (C) 2016 Elsevier Ltd. All rights reserved.
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