Synthesis of new benzimidazole-coumarin conjugates as anti-hepatitis C virus agents.
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.
Hwu
Jih Ru
JR
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC. jrhwu@mx.nthu.edu.tw
Singha
Raghunath
R
Hong
Shih Ching
SC
Chang
Yung Hsiung
YH
Das
Asish R
AR
Vliegen
Inge
I
De Clercq
Erik
E
Neyts
Johan
J
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D015394:Molecular Structure; D012367:RNA, Viral / Q000235:genetics; D013329:Structure-Activity Relationship; D014780:Viruses / Q000187:drug effects
D000998:Antiviral Agents; D001562:Benzimidazoles; D003374:Coumarins; D012367:RNA, Viral; C030123:coumarin; C031000:benzimidazole