title: Design, synthesis, anticoagulant activity evaluation and molecular docking studies of a class of N-ethyl dabigatran derivatives.
abstract: A class of N-ethyl dabigatran derivatives was designed based on pharmacological strategies for inhibition of thrombin activity and the structure-activity relationship studies of the previous dabigatran derivatives. Activities of these novel compounds were predicted based on CoMFA model, and most of the compounds had comparable predicted activity with dabigatran. All of screened compounds were synthesized and characterized by (1)H NMR, (13)C NMR and HRMS. Subsequently, these compounds were evaluated inhibitory activity on thrombin. Among these compounds, 9a-9e, 9h, 9l-9n and 9p exhibited comparable inhibitory activity to dabigatran (IC50 = 1.20 nM), additionally, compound 9p (IC50 = 0.96 nM) exhibited better inhibitory activity than dabigatran. Moreover, compound 9p also exhibited a fairly good inhibitory activity for arteriovenous thrombosis with inhibition rate of (85.35 ± 0.72) %, which was comparable to that of dabigatran (85.07 ± 0.61) %. These results, along with related molecular docking studies, could provide an important basis for further development of compound 9p as a potent thrombin inhibitor.
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Weixin
authors.initials: W
authors.lastname: Ren
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: Shuai
authors.initials: S
authors.lastname: Wang
mesh_terms: D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D000991:Antithrombins / Q000737:chemistry*; D000069604:Dabigatran / Q000031:analogs & derivatives* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D000069604:Dabigatran
keywords: Anticoagulant activity; Molecular docking; N-methyl dabigatran derivatives; Synthesis