Benzimidazole inhibitors of hepatitis C virus NS5B polymerase: identification of 2-[(4-diarylmethoxy)phenyl]-benzimidazole.
A series of 1-cycloalkyl-2-phenyl-1H-benzimidazole-5-carboxylic acid derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase (RdRp). A SAR study was performed and led to identify the 2-[(4-diarylmethoxy)phenyl]-benzimidazoles as potent inhibitors. They inhibit subgenomic HCV RNA replication in the replicon cells at low micromolar concentrations (EC(50) as low as 1.1microM). They are selective against DNA polymerases (IC(50)>10microM) and exhibit low cytotoxicity.
Ishida
Tomio
T
Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Suzuki
Takayoshi
T
Hirashima
Shintaro
S
Mizutani
Kenji
K
Yoshida
Atsuhito
A
Ando
Izuru
I
Ikeda
Satoru
S
Adachi
Tsuyoshi
T
Hashimoto
Hiromasa
H
D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase