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.
Highlights
IntroductionChlorine atom increased the activity 6-fold (compound Z385), a fluorine atom – nearly 5 times (compound Z414), methyl group − 10 times (Compound Z413) as compared to the unsubstituted compound Z263
Introduction of theR3 substituent proved to have a favorable effect
Synthesis of the starting uracil derivatives 1 was described previously20. 2-Chloro-N(4-phenoxyphenyl)acetamides and their analogues 2 were prepared according to earlier published method[21]
Summary
Chlorine atom increased the activity 6-fold (compound Z385), a fluorine atom – nearly 5 times (compound Z414), methyl group − 10 times (Compound Z413) as compared to the unsubstituted compound Z263. For the latter two cases, there was a two-fold increase in cytotoxicity. The study of influence of the nature of the linker fragment Y showed that optimal virus-inhibitory properties can be achieved with a methylene group (Z387). It provides the best activity and selectivity among the tested oxygen atom (Z263), carbonyl (Z430), or oxymethylene group (Z377). Due to the high cytotoxicity compound has a low SI
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