title: Design, synthesis, and anti-thrombotic evaluation of some novel fluorinated thrombin inhibitor derivatives.
abstract: Computer-aided simulation was used to design and synthesize nine novel fluorinated thrombin inhibitor derivatives. These compounds were confirmed by spectral analyses ((1)H NMR, (13)C NMR, and FT-ICR-MS). Their inhibitory activities against thrombin enzyme were evaluated by chromogenic assay. All the derivatives demonstrated thrombin inhibitory activity in vitro. Five of these compounds exerted more potent effects against thrombin enzyme compared with the reference drug argatroban. Compound 3-(2-(((4-carbamimidoylphenyl)amino)methyl)-1-ethyl-N-(2-fluoro-phenyl)-1H-benzo[d]imidazole-5-carboxamido)propanoic acid (IC50 = 3.52 ± 0.32 nmol/L) was a more potent inhibitor of thrombosis than argatroban (IC50 = 9.46 ± 0.92 nmol/L).
authors.affiliation: College of Chemistry and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Chen
authors.affiliation: College of Chemistry and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Ren
mesh_terms: D000991:Antithrombins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001665:Binding Sites; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D017076:Computer-Aided Design; D015195:Drug Design; D054879:Halogenation; D006801:Humans; D013058:Mass Spectrometry; D062105:Molecular Docking Simulation; D010875:Pipecolic Acids / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D066244:Proton Magnetic Resonance Spectroscopy; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000991:Antithrombins; D010875:Pipecolic Acids; D011422:Propionates; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; C031942:argatroban
keywords: Argatroban; Chromogenic assay; Docking; Fluorine; Thrombin inhibitor