title: Design, synthesis and structural exploration of novel fluorinated dabigatran derivatives as direct thrombin inhibitors.
abstract: Twenty-one fluorinated dabigatran derivatives were designed based on the bioisosteric principle. All derivatives were synthesised and evaluated for their thrombin inhibitory activity in vitro. Among these compounds, 14h, 14m, 14s and 14t were potent and the activity was in the range of reference drug, dabigatran. Three structural changes were introduced in these 21 compounds to elucidate the structure-activity relationship of the drugs. In addition, prodrugs of compounds 14h and 14s were developed to investigate their anticoagulant activities in vivo. In these experiments, compound 16 showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and demonstrated potent activity for inhibiting arteriovenous thrombosis with an inhibition rate of (73 ± 6) %, which was comparable to that of dabigatran etexilate (76 ± 2) %. Moreover, molecular docking studies were performed to understand the binding interactions of active compounds 14h, 14s and 14t with thrombin protein (PDB ID:1KTS). Contour maps obtained from the 3D-QSAR model are meaningful in designing more active molecules to act as direct inhibitors of thrombin.
authors: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors: Mei-Lin
authors: ML
authors: Li
authors: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China. Electronic address: clab@sit.edu.cn.
authors: Yu-Jie
authors: YJ
authors: Ren
authors: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors: Ming-Hui
authors: MH
authors: Dong
authors: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China.
authors: Wei-Xin
authors: WX
authors: Ren
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D000069604:Dabigatran / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D006845:Hydrocarbons, Fluorinated; D013917:Thrombin; D000069604:Dabigatran
keywords: Anticoagulant activity; Computer-aided simulation; Fluorinated dabigatran derivatives; Synthesis