title: Exploration of acetanilide derivatives of 1-(ω-phenoxyalkyl)uracils as novel inhibitors of Hepatitis C Virus replication.
abstract: Hepatitis C Virus (HCV) is a major public health problem worldwide. While highly efficacious directly-acting antiviral agents have been developed in recent years, their high costs and relative inaccessibility make their use limited. Here, we describe new 1-(ω-phenoxyalkyl)uracils bearing acetanilide fragment in 3 position of pyrimidine ring as potential antiviral drugs against HCV. Using a combination of various biochemical assays and in vitro virus infection and replication models, we show that our compounds are able to significantly reduce viral genomic replication, independently of virus genotype, with their IC50 values in the nanomolar range. We also demonstrate that our compounds can block de novo RNA synthesis and that effect is dependent on a chemical structure of the compounds. A detailed structure-activity relationship revealed that the most active compounds were the N(3)-substituted uracil derivatives containing 6-(4-bromophenoxy)hexyl or 8-(4-bromophenoxy)octyl fragment at N(1) position.
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.|Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.|Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Magri
authors.affiliation: Department of Pharmaceutical &Toxicological Chemistry, Volgograd State Medical University, Volgograd, Russia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Ozerov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow, Russia.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Tunitskaya
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow, Russia.
authors.forename: Vladimir T
authors.initials: VT
authors.lastname: Valuev-Elliston
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.|Department of Biochemistry, Faculty of Pharmacy, Minia, University, Minia, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Wahid
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Pirisi
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Simmonds
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ivanov
authors.affiliation: Department of Pharmaceutical &Toxicological Chemistry, Volgograd State Medical University, Volgograd, Russia.
authors.forename: Mikhail S
authors.initials: MS
authors.lastname: Novikov
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000187:drug effects; D057809:HEK293 Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D012367:RNA, Viral / Q000235:genetics; D013329:Structure-Activity Relationship; D014498:Uracil / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000083:Acetanilides; D000998:Antiviral Agents; D012367:RNA, Viral; D014498:Uracil