ABSTRACT
For establishment of the structure-activity relationship, 19 heterobicycle-coumarin conjugated compounds with the -SCH(2)- linker were synthesized and found to possess significant antiviral activities. Prominent examples included imidazopyridine-coumarin 12c, purine-coumarin 12d, and benzoxazole-coumarin 14c, which inhibited HCV replication at an EC(50) of 6.8, 2.0, and 12 microM, respectively. The heteroatoms in bicycles and the substituent effect on coumarin played essential roles.
Subject(s)
Antiviral Agents/chemical synthesis , Coumarins/chemical synthesis , Hepacivirus/drug effects , Heterocyclic Compounds, 2-Ring/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Cell Line , Cell Proliferation/drug effects , Coumarins/chemistry , Coumarins/pharmacology , Hepacivirus/genetics , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Models, Molecular , Purines/chemical synthesis , Purines/chemistry , Purines/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , RNA, Viral/drug effects , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Nineteen new conjugated compounds were successfully synthesized by a one-flask method from benzimidazole and coumarin derivatives. A methylenethio linker was used to connect these two kinds of derivatives. In addition, substituted benzimidazol-2-thiones were also coupled with beta-D-glucose peracetate; the resultant glucosides were further converted to the corresponding 2-(methylthio)coumarin derivatives. Their activity against the hepatitis C virus was tested; two of the most potent compounds 2-[(6'-bromocoumarin-3'-yl)methylenethio]-5-fluorobenzimidazole (4i) and its derivative 1-[(2'',3'',4'',6''-tetra-O-acetyl)glucopyranos-1''-yl]-2-[(6'-bromocoumarin-3'-yl)methylenethio]benzimidazole (7c) showed EC(50) values of 3.4 microM and 4.1 microM, respectively. At a concentration of 5.0 microM, compound 7c inhibited HCV RNA replication by 90% and had no effect on cell proliferation. Given these data, a structure-activity relationship was established.
