Discovery of Metal Ions Chelator Quercetin Derivatives with Potent Anti-HCV Activities

Analogues or isosteres of α,γ-diketoacid (DKA) 1a show potent inhibition of hepatitis C virus (HCV) NS5B polymerase through chelation of the two magnesium ions at the active site. The anti-HCV activity of the flavonoid quercetin (2) could partly be attributed to it being a structural mimic of DKAs. In order to delineate the structural features required for the inhibitory effect and improve the anti-HCV potency, two novel types of quercetin analogues, 7-O-arylmethylquercetins and quercetin-3-O-benzoic acid esters, were designed, synthesized and evaluated for their anti-HCV properties in cell-based assays. Among the 38 newly synthesized compounds, 7-O-substituted derivative 3i and 3-O-substituted derivative 4f were found to be the most active in the corresponding series (EC50 = 3.8 μM and 9.0 μΜ, respectively). Docking studies suggested that the quercetin analogues are capable of establishing key coordination with the two magnesium ions as well as interactions with residues at the active site of HCV NS5B.

[1]  Jui-Yuan Lee,et al.  Design and Synthesis , 2015 .

[2]  F. A. Khan,et al.  Pharmacological Applications of Quercetin and its Derivatives: A Short Review , 2014 .

[3]  J. Pawlotsky,et al.  Inhibition of RNA binding to hepatitis C virus RNA-dependent RNA polymerase: a new mechanism for antiviral intervention , 2014, Nucleic acids research.

[4]  Jian-Ping Zuo,et al.  Discovering novel anti-HCV compounds with inhibitory activities toward HCV NS3/4A protease , 2014, Acta Pharmacologica Sinica.

[5]  R. Steinbrook,et al.  The high price of the new hepatitis C virus drugs. , 2014, JAMA internal medicine.

[6]  B. Samuelsson,et al.  Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor. , 2014, Journal of medicinal chemistry.

[7]  T. Asselah.  Sofosbuvir for the treatment of hepatitis C virus , 2014, Expert opinion on pharmacotherapy.

[8]  A. Flaxman,et al.  Global epidemiology of hepatitis C virus infection: New estimates of age‐specific antibody to HCV seroprevalence , 2013, Hepatology.

[9]  J. Duan,et al.  Metabolism-based synthesis, biologic evaluation and SARs analysis of O-methylated analogs of quercetin as thrombin inhibitors. , 2012, European journal of medicinal chemistry.

[10]  Wei Li,et al.  Discovery of flavonoid derivatives as anti-HCV agents via pharmacophore search combining molecular docking strategy. , 2012, European journal of medicinal chemistry.

[11]  Patricia Hurter,et al.  Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus , 2011, Nature Biotechnology.

[12]  M. Imamura,et al.  Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo , 2011, Hepatology.

[13]  Xinwen Chen,et al.  Compensatory mutations in NS3 and NS5A proteins enhance the virus production capability of hepatitis C reporter virus. , 2009, Virus research.

[14]  P. Kwo,et al.  Boceprevir, an NS3 protease inhibitor of HCV. , 2009, Clinics in liver disease.

[15]  Yong‐Joo Jeong,et al.  Investigation of the pharmacophore space of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) NTPase/helicase by dihydroxychromone derivatives , 2009, Bioorganic & Medicinal Chemistry Letters.

[16]  Weiliang Zhu,et al.  Discovering novel quercetin-3-O-amino acid-esters as a new class of Src tyrosine kinase inhibitors , 2008, European Journal of Medicinal Chemistry.

[17]  B. Haagmans,et al.  Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-alpha. , 2006, Gastroenterology.

[18]  M. Rowley,et al.  4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species. , 2006, Journal of medicinal chemistry.

[19]  J. Hoofnagle,et al.  Mechanism of action of interferon and ribavirin in treatment of hepatitis C , 2005, Nature.

[20]  R. Francesco,et al.  HCV NS5b RNA-Dependent RNA Polymerase Inhibitors: From α,γ-Diketoacids to 4,5-Dihydroxypyrimidine- or 3-Methyl-5- hydroxypyrimidinonecarboxylic Acids. Design and Synthesis , 2004 .

[21]  R. De Francesco,et al.  The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase. , 2004, Bioorganic & medicinal chemistry letters.

[22]  Uwe Koch,et al.  Discovery of α,γ-Diketo Acids as Potent Selective and Reversible Inhibitors of Hepatitis C Virus NS5b RNA-Dependent RNA Polymerase , 2004 .

[23]  Dieter Häussinger,et al.  Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. , 2002, The New England journal of medicine.

[24]  F. Rey,et al.  Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides , 2002, Journal of Virology.

[25]  N. Habuka,et al.  Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus. , 1999, Structure.