Design, Synthesis and Bioactivity Evaluation of Novel Dabigatran Derivatives as Potential Thrombin Inhibitors

With the help of computer-aided drug design approach, five dabigatran derivatives were designed and synthesized. The structures of these compounds were elucidated by 1H NMR, 13C NMR, HRMS analyses. All the compounds were evaluated for their thrombin inhibitory activitiy in vitro (IC50) and they showed significant thrombin inhibition with IC50 values from 2.74 to 20.31 nM. Especially, compound 7a, and 7b were potent thrombin inhibitor with IC50 values of 2.74 and 2.99 nM, respectively, which were comporable to dabigatran (1.20 nM) and much better than argatroban (9.88 nM). Moreover, molecular docking study was performed to determine the inhibitory mechanism of active compounds.