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JAC Advance Access originally published online on March 2, 2005
Journal of Antimicrobial Chemotherapy 2005 55(4):483-488; doi:10.1093/jac/dki055
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions{at}oupjournals.org

Novel [(biphenyloxy)propyl]isoxazole derivatives for inhibition of human rhinovirus 2 and coxsackievirus B3 replication

Vadim A. Makarov1, Olga B. Riabova1, Vladimir G. Granik1, Peter Wutzler2 and Michaela Schmidtke2,*

1 Department of Medicinal Chemistry, Research Center for Antibiotics, Nagatinskaya Street 3a, Moscow, 117105, Russia; 2 Institute of Virology and Antiviral Therapy, Friedrich Schiller University, Hans-Knoell-Strasse 2, Jena, D-07745, Germany

* Corresponding author. Tel: +49-3641-657222; Fax: +49-3641-657202; Email: michaela.schmidtke{at}med.uni-jena.de

Objectives: During this study, novel biphenyl derivatives were synthesized and tested for antiviral activity.

Methods: A new method based on the Suzuki coupling reaction has been established for the synthesis of these polysubstituted chain systems. In parallel with cytotoxicity, the antiviral activity of biphenyl derivatives has been determined in cytopathic effect (CPE)-inhibitory assays with the pleconaril-resistant coxsackievirus B3 (CVB3) strain Nancy, human rhinovirus 2 (HRV-2) and 14 (HRV-14) and in plaque reduction assays with the pleconaril-sensitive human isolate CVB3 97-927 in HeLa cells. Based on the results from these investigations the selectivity index (SI) was determined as the ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration.

Results: The new method based on the Suzuki coupling reaction includes the condensation of 2,6-dimethyl-4-bromophenol with pentyne chloride by means of potassium carbonate and potassium iodide in N-methylpyrrolidone-2 and yields 5-bromo-1,3-dimethyl-2-(4-pentynyloxy)benzene. Its condensation with methylacetaldoxime results in 3-methylisoxazole derivatives. The following reaction with different benzeneboronic acids by means of tetrakis(triphenylphosphine)-palladium(0) finally yields the corresponding derivatives. Several of the novel synthesized derivatives demonstrated a good antiviral activity on CVB3 (SI > 2 to > 37.5) and a strong anti-HRV-2 activity (SI > 50 to > 200). In contrast, none of the compounds inhibited the HRV-14-induced CPE.

Conclusions: These results indicate that [(biphenyloxy)propyl]isoxazole derivatives are potential inhibitors of HRV-2 and CVB3 replication, and make them promising agents for the specific treatment of these virus infections.

Keywords: antivirals , biphenyls , Suzuki reaction , picornaviruses , rhinoviruses , coxsackieviruses


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M. Schmidtke, E. Hammerschmidt, S. Schuler, R. Zell, E. Birch-Hirschfeld, V. A. Makarov, O. B. Riabova, and P. Wutzler
Susceptibility of coxsackievirus B3 laboratory strains and clinical isolates to the capsid function inhibitor pleconaril: antiviral studies with virus chimeras demonstrate the crucial role of amino acid 1092 in treatment
J. Antimicrob. Chemother., October 1, 2005; 56(4): 648 - 656.
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