title: Synthesis and Biological Evaluation of Some New 2,5-Substituted 1-Ethyl-1H-benzoimidazole Fluorinated Derivatives as Direct Thrombin Inhibitors.
abstract: A new series of fluorinated 2,5-substituted 1-ethyl-1H-benzimidazole derivatives were synthesized from starting compounds 3a-i, which were prepared from acrylic acid ethyl ester and the appropriate amines using trifluoromethanesulfonic acid as a catalyst. A total of 9 novel derivatives were synthesized through 9 steps. All of them were evaluated for thrombin inhibition activity in vitro for the first time. We have altered their structures using different substituents on the amines to assess their structure-activity relationships as direct thrombin inhibitors. All the compounds were effective thrombin inhibitors, with IC50 values ranging from 3.39 to 23.30 nM. Among the compounds synthesized, compounds 14a, 14b, 14d, 14e, and 14h exhibited greater anticoagulant activity than argatroban (IC50 = 9.36 nM). Furthermore, compound 14h synthesized starting with 2-amino-pyridine was the most potent thrombin inhibitor with an IC50 value of 3.39 nM. Molecular modeling studies were performed to determine the probable interactions of the most potent compounds 14a, 14e, and 14h with their protein receptor (PDB ID: 1KTS). Docking data show that the active compounds inhibit thrombin in a similar mode to that of the potent anticoagulant dabigatran.
authors.affiliation: College of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Li
authors.forename: Yujie
authors.initials: Y
authors.lastname: Ren
mesh_terms: D000991:Antithrombins / Q000138:chemical synthesis* / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D000069604:Dabigatran / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010875:Pipecolic Acids / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D006845:Hydrocarbons, Fluorinated; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D000069604:Dabigatran; C031942:argatroban
keywords: 1-Ethyl-1H-benzoimidazole fluorinated derivatives; Direct thrombin inhibitors; Molecular docking; Synthesis