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Molecules 2008, 13(5), 1081-1110; doi:10.3390/molecules13051081
Article

Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization

1, 1, 1, 1, 2, 2, 3, 1 and 1,*
1 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany 2 Department of Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 345, D-69120 Heidelberg, Germany 3 Endotherm GmbH, Science-Park II, D-66123 Saarbrücken, Germany
* Author to whom correspondence should be addressed.
Received: 26 March 2008 / Revised: 2 May 2008 / Accepted: 7 May 2008 / Published: 7 May 2008
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Abstract

Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27% inhibition) of the CD81-LEL–HCV-E2 interaction. To increase the observed biologicalactivity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilicsubstitution. The prepared compounds were tested for their inhibitory potency by means ofa fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activityrelationships could be derived. Optimization was successful, leading to 3g, identfied as themost potent compound (69 % inhibition). Experiments with viral particles revealed thatthere might be additional HCV infection reducing mechanisms.
Keywords: Hepatitis C Virus; CD81-receptor; large extracellular loop; terfenadine derivatives; microwave assisted syntheses. Hepatitis C Virus; CD81-receptor; large extracellular loop; terfenadine derivatives; microwave assisted syntheses.
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Holzer, M.; Ziegler, S.; Albrecht, B.; Kronenberger, B.; Kaul, A.; Bartenschlager, R.; Kattner, L.; Klein, C.D.; Hartmann, R.W. Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization. Molecules 2008, 13, 1081-1110.

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