| Thrombosis is one of the main causes of high-frequency morbidity and mortality in people around the world.Among them,thrombin plays an important role in the formation of blood clots in the body.Therefore,it is used clinically to treat thrombotic diseases by inhibiting the activity of thrombin.Among the numerous direct antithrombin inhibitor drugs,dabigatran etexilate is the first new oral direct antithrombin inhibitor to be marketed within 50years after warfarin is on the market,with advantages of oral,strong efficacy,no need for special drug monitoring,less drug interactions,and relatively high security.Therefore,the related work on the modification of the structure of dabigatran etexilate has also received extensive attention from scientists.Since dabigatran is the prodrug of dabigatran etexilate,in this paper,eight novel derivatives containing chloridabigatran benzimidazole-propyl substituents were screened by computer aided drug design principle,and the designed target compounds were synthesized.The target compounds 12a-12h were synthesized from aniline,ethyl acrylate,4-chloro-3-nitroformic acid and propylamine after nine steps of chemical reactions,including Michael addition,amidation,reduction,condensation closed-loop reaction,Pinner reaction and hydrolysis.All target compounds were characterized by 1H NMR spectrum,13C NMR spectrum and LC-MS.And the thrombin inhibitory activity of compound 12a-12h was tested in vitro by National Center for New Drug Screening.The results showed that the activity of all the designed target compounds was similar to that of the positive compound dabigatran(IC50 value:1.19±0.09 n M),and the activity order was 12b>12h>12g>12a>12c>12e>12f>12d.Among them,compound 12b（1.26±0.16 n M）showed superior biological activity compared with argatroban.In this study,eight candidate compounds with novel structures were synthesized,which could be used as potential thrombin inhibitors for further study. |
