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JAC Advance Access published online on December 30, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki481
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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@oxfordjournals.org
Received July 7, 2005
Revised October 14, 2005
Accepted December 12, 2005

Original article

Pyridine N-oxide derivatives are inhibitory to the human SARS and feline infectious peritonitis coronavirus in cell culture

Jan Balzarini 1 *, Els Keyaerts 1, Leen Vijgen 1, Frank Vandermeer 2, Miguel Stevens 1, Erik De Clercq 1, Herman Egberink 2, and Marc Van Ranst 1

1 Rega Institute for Medical Research, K.U. Leuven, Leuven, Belgium
2 Institute of Virology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

* To whom correspondence should be addressed.
Jan Balzarini, E-mail: jan.balzarini{at}rega.kuleuven.ac.be


  Abstract

Objectives: Evaluation of a wide variety of pyridine N-oxide derivatives on their inhibitory activity against feline coronavirus (FIPV strain) and human SARS-CoV (Frankfurt strain-1) in cell culture.

Methods: FIPV and SARS-CoV were exposed to confluent Crandel feline kidney (CRFK) and simian kidney (Vero) cell cultures in the presence of serial concentrations of the test compounds. The anti-cytopathic activity of the pyridine N-oxide derivatives was monitored by spectrophotometric analysis.

Results and conclusions: A wide variety of pyridine N-oxide derivatives have been found to be inhibitory against feline coronavirus (FIPV strain) and human SARS-CoV (Frankfurt strain-1) in CRFK and simian kidney (Vero) cell cultures, respectively. The oxide part on the pyridine moiety proved indispensable for anti-coronavirus activity. The potency and virus specificity of the pyridine N-oxide derivatives varied depending the nature and specific location of substituents (i.e. alkyl, halogeno, nitro, etc.) on the different parts of the molecule. The most selective compounds were active in the higher microgram per litre range, being non-toxic at 50-100 mg/L. There was a poor structure-antiviral activity relationship (SAR) for the pyridine N-oxide derivatives against Fe-CoV and SARS-CoV. One of the most active and selective compounds was shown to inhibit Fe-CoV replication at the transcriptional level.

Keywords: severe acute respiratory syndrome; feline coronavirus; FIPV.
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