Synthesis of new acridone derivatives, inhibitors of NS3 helicase, which efficiently and specifically inhibit subgenomic HCV replication
- PMID: 20337460
- DOI: 10.1021/jm901741p
Synthesis of new acridone derivatives, inhibitors of NS3 helicase, which efficiently and specifically inhibit subgenomic HCV replication
Abstract
A new goup of acridone derivatives, obtained by reaction of acridone-4-carboxylic acid derivatives with aromatic amines, was tested to determine the inhibitory properties toward the NS3 helicase of hepatitis C virus (HCV). Six compounds inhibited the NS3 helicase at low concentrations (IC(50) from 1.5 to 20 microM). The acridone derivatives probably act via intercalation into double-stranded nucleic acids with a strong specificity for double-stranded RNA, although an interaction with the enzyme cannot be excluded. Testing in the subgenomic HCV replicon system revealed that compounds 10 and 13 are efficient RNA replication inhibitors, with EC(50) of 3.5 and 1 microM and therapeutic indexes of >28 and 20, respectively. Compound 16, with EC(50) < 1 microM and TI > 1000, is extremely specific and practically noncytotoxic at the concentrations tested, proving that the acridone derivatives may be regarded as potential antiviral agents. Although the mechanism of action of 16 in the replicon system remains unclear, it is the key lead compound for further development of anti-HCV drugs.
Similar articles
-
Acridones as antiviral agents: synthesis, chemical and biological properties.Curr Med Chem. 2013;20(19):2402-14. doi: 10.2174/0929867311320190002. Curr Med Chem. 2013. PMID: 23521684 Review.
-
Studies on the anti-hepatitis C virus activity of newly synthesized tropolone derivatives: identification of NS3 helicase inhibitors that specifically inhibit subgenomic HCV replication.Bioorg Med Chem. 2010 Jul 15;18(14):5129-36. doi: 10.1016/j.bmc.2010.05.066. Epub 2010 Jun 2. Bioorg Med Chem. 2010. PMID: 20579888
-
Inhibition of subgenomic hepatitis C virus RNA replication by acridone derivatives: identification of an NS3 helicase inhibitor.J Med Chem. 2009 May 28;52(10):3354-65. doi: 10.1021/jm801608u. J Med Chem. 2009. PMID: 19388645
-
New acridone-4-carboxylic acid derivatives as potential inhibitors of hepatitis C virus infection.Bioorg Med Chem. 2008 Oct 1;16(19):8846-52. doi: 10.1016/j.bmc.2008.08.074. Epub 2008 Aug 31. Bioorg Med Chem. 2008. PMID: 18801660
-
Structure and function of hepatitis C virus NS3 helicase.Curr Top Microbiol Immunol. 2000;242:171-96. doi: 10.1007/978-3-642-59605-6_9. Curr Top Microbiol Immunol. 2000. PMID: 10592661 Review.
Cited by
-
Acridones as promising drug candidates against Oropouche virus.Curr Res Microb Sci. 2023 Dec 23;6:100217. doi: 10.1016/j.crmicr.2023.100217. eCollection 2024. Curr Res Microb Sci. 2023. PMID: 38234431 Free PMC article.
-
Boron Trifluoride Etherate Promoted Microwave-Assisted Synthesis of Antimalarial Acridones.RSC Adv. 2019;9(72):42284-42293. doi: 10.1039/c9ra09478d. Epub 2019 Dec 20. RSC Adv. 2019. PMID: 35321096 Free PMC article.
-
Acridone suppresses the proliferation of human breast cancer cells in vitro via ATP-binding cassette subfamily G member 2.Oncol Lett. 2018 Feb;15(2):2651-2654. doi: 10.3892/ol.2017.7583. Epub 2017 Dec 11. Oncol Lett. 2018. PMID: 29434987 Free PMC article.
-
Multiple effects of toxins isolated from Crotalus durissus terrificus on the hepatitis C virus life cycle.PLoS One. 2017 Nov 15;12(11):e0187857. doi: 10.1371/journal.pone.0187857. eCollection 2017. PLoS One. 2017. PMID: 29141010 Free PMC article.
-
Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4.J Gen Virol. 2017 Jul;98(7):1693-1701. doi: 10.1099/jgv.0.000808. Epub 2017 Jul 12. J Gen Virol. 2017. PMID: 28699869 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources