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Imidazoquinoline derivatives:
design, synthesis and evaluation of their in vitro anti-Flaviviridae activity
Scuola di dottorato di ricerca in Scienze e Tecnologie Chimiche, indirizzo Scienze Farmaceutiche Dipartimento di Scienze del Farmaco, via Muroni 23a, 07100, Sassari, Italy
Background - The Flaviviridae family comprises three genera belonging to viruses with single-stranded positive-sense
RNA genomes (ssRNA+) that cause significant diseases in human and animal populations. The hepatitis C virus (HCV),
included in the Hepacivirus genus, is a major cause of human hepatitis, globally. Chronic HCV infection can lead to
development of cirrhosis, hepatocellular carcinoma and liver failure.1 Pegylated interferon in combination with ribavirin
is used in the clinic for hepatitis due to HCV. Unfortunately, this therapy has limited efficacy and is often associated
with severe and adverse events.
Aims - In the aim to find new and more effective compounds endowed with anti-HCV activity, we studied various
series of linear aromatic N-tricyclic systems, derived from the quinoline ring. In particular, we have studied
triazolo[4,5-g]quinolines,
imidazoquinoline 1 and 2 stood out for their anti-Flaviviridae activities, showing a potent and selective activity against
the RNA-dependent RNA polymerase (RdRp), termed NS5B in the case of both Hepaciviruses and Pestiviruses. In this
work we have proceeded in synthesizing derivatives of molecular simplification and bioisosteric substitution in order to
identify the structural components essential or modulating the biological activity. Design criteria are showed in the
Scheme.
Results – All products showed in the Scheme
have been evaluated for antiviral activity, and
parallel cell-based essays were performed in
order to evaluate their cytotoxicity. The activity
analysis was conducted against both BVDV and a
large panel of other viruses.
Bearing in mind that the lead compound 1 has
showed an EC50 on BVDV equal to 0.3 µM and a
CC50 on MT-4 of 69 µM, the results of biological
screening studies and cytotoxicity of the new
molecules demonstrate that all the products of
molecular simplification shown drastic reduction
of power, including compounds which exhibit
lower citotoxicity than the reference compound!
Consequently, this molecules did not form the
subject of future studies as anti-HCV agents,
however, they allow us to make some important
inferences about the SAR of the lead. We also
find an interesting activity of some derivatives against other major pathogenic viruses. Finally, molecular modeling
studies are trying to identify the binding site and mode of action of the lead compound against the RdRp NS5B of
BVDV and HCV.
References
1. Bosch, F. X.; Ribes, J.; Cleries, R.; Diaz, M. Epidemiology of hepatocellular carcinoma. Clin. LiverDis. 2005, 9,
2. Carta, A.; Vitale, G.; Piras, S.; Sias, A.; Corona, P.; Paglietti, G. QuinolineTricyclicDerivatives. Design, Synthesis and Preliminary In vitro and In silicoAntiviral Activity Against Flaviviridae Family of Three New Classes of Virus-Encoded RNA-Dependent RNA Polymerase (RdRp) Inhibitors, XIX National Meeting on Medicinal Chemistry, Verona, 14-18 Settembre 2008, Atti, P-091, p. 179. 3. Carta, A.; Palomba, M.; Corona P. Synthesis of substituted aminoquinolines as useful intermediates for preparation of aromatic N-tricyclic systems. Heterocycles, 2006, 68, 1715-1722.

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