title: Anti-hepatitis C virus RdRp activity and replication of novel anilinobenzothiazole derivatives.
abstract: Hepatitis C virus (HCV) infection is a worldwide health problem. This can be attributed, in part, to the high mutation rate associated with RNA viral replication, which favors the emergence of drug resistance and limits the efficacy of current therapies. Here we report the continuation of our efforts to rationally design and synthesize a series of novel anilinobenzothiazole derivatives. We demonstrate that 2-(4-nitroanilino)-6-methylenzothiazole (compound 14) inhibited HCV RNA-dependent RNA polymerase (RdRp) activity and HCV RNA replication (EC50=8±0.5μM) in a dose-dependent manner, consistent with a noncompetitive model of inhibition (kinetic constant Ki=7.76μM). The best docking pose of compound 14 is located in the Thumb II Pocket, suggesting an inhibitory mechanism involving the docking of compound 14 that alters RdRp breathing. Combinations of compound 14 with interferon-α or other drugs potentially targeting HCV proteins, including telaprevir, PSI7977, or BMS790052, synergistically decreased the levels of HCV RNA.
authors.affiliation: School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Huang-Kai
authors.initials: HK
authors.lastname: Peng
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chen
authors.forename: Ying-Ting
authors.initials: YT
authors.lastname: Lin
authors.forename: Chin-Kai
authors.initials: CK
authors.lastname: Tseng
authors.forename: Shiang-Yu
authors.initials: SY
authors.lastname: Yang
authors.forename: Cherng-Chyi
authors.initials: CC
authors.lastname: Tzeng
authors.forename: Jin-Ching
authors.initials: JC
authors.lastname: Lee
authors.forename: Shyh-Chyun
authors.initials: SC
authors.lastname: Yang
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase; C005465:benzothiazole
keywords: Anilinobenzothiazole; Hepatitis C virus; RNA-dependent RNA polymerase