Design, synthesis and biological activity evaluation of novel methyl substituted benzimidazole derivatives

摘要

Ten new dabigatran derivatives (7a-j) with high docking scoring were designed, synthesised and biologically evaluated. The inhibitory in vitro activity of these compounds on thrombin was evaluated on the basis of preliminary activity screening results. The IC50 values of compounds 7a, 7d and 7j were 1.92, 2.17 and 1.54 nM, respectively, and are equivalent to the dabigatran (IC50 = 1.20 nM). Therefore, the most active compound, 7j, was selected to further investigate the anticoagulant activity in rats. Compound 7j presented excellent in vivo inhibitory effects on arteriovenous thrombosis, and the inhibition rate was (84.19 +/- 1.14) %. The anticoagulant activity of compound 7k synthesised in the previous work was evaluated in vivo, and its inhibition rate was (85.58 +/- 2.89) %. This rate was nearly equivalent to that of dabigatran (85.07 +/- 0.61) %. Results indicated that compounds 7a, 7d, 7j and 7k can be further studied as novel antithrombin drug candidates. (C) 2020 Elsevier Ltd. All rights reserved.