Exploration of acetanilide derivatives of 1-(ω-phenoxyalkyl)uracils as novel inhibitors of Hepatitis C Virus replication

Magri, A., Ozerov, A. A., Tunitskaya, V. L., Valuev-Elliston, V. T., Wahid, A., Pirisi, M., Simmonds, P., Ivanov, A. V., Novikov, M. S. and Patel, A. H. (2016) Exploration of acetanilide derivatives of 1-(ω-phenoxyalkyl)uracils as novel inhibitors of Hepatitis C Virus replication. Scientific Reports, 6, 29487. (doi: 10.1038/srep29487) (PMID:27406141) (PMCID:PMC4942610)

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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 N3-substituted uracil derivatives containing 6-(4-bromophenoxy)hexyl or 8-(4-bromophenoxy)octyl fragment at N1 position.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Patel, Professor Arvind and Magri, Mr Andrea
Authors: Magri, A., Ozerov, A. A., Tunitskaya, V. L., Valuev-Elliston, V. T., Wahid, A., Pirisi, M., Simmonds, P., Ivanov, A. V., Novikov, M. S., and Patel, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Published Online:12 July 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Scientific Reports 6:29487
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656491Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2MVLS III - CENTRE FOR VIRUS RESEARCH