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Quinoline tricyclic derivatives: design, synthesis and evaluation of the antiviral activity of three new classes of RNA-dependent RNA polymerase inhibitors

By Antonio Carta, Irene Briguglio, Sandra Piras, Paola Corona, Gianpiero Boatto, Maria Nieddu, Paolo Giunchedi, Maria Elena Marongiu, Gabriele Giliberti, Filippo Iuliano, Sylvain Blois, Cristina Ibba, Bernardetta Busonera and Paolo La Colla


In this study three new classes of linear <i>N</i>-tricyclic compounds, derived by condensation of the quinoline nucleus with 1,2,3-triazole, imidazole or pyrazine, were synthesized, obtaining triazolo[4,5-<i>g</i>]quinolines, imidazo[4,5-<i>g</i>]quinolines and pyrido[2,3-<i>g</i>]quinoxalines, respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA viruses representative of the three genera of the <i>Flaviviridae</i> family, that is BVDV (<i>Pestivirus</i>), YFV (<i>Flavivirus</i>) and HCV (<i>Hepacivirus</i>). Quinoline derivatives were also tested against representatives of other RNA virus families containing single-stranded, either positive-sense (ssRNA<sup>+</sup>) or negative-sense (RNA<sup>−</sup>), and double-stranded genomes (dsRNA), as well as against representatives of two DNA virus families. Some quinolines showed moderate, although selective activity against CVB-5, Reo-1 and RSV. However, derivatives belonging to all classes showed activity against BVDV. Among the most potent were the bis-triazoloquinoline <b>1m</b>, the imidazoquinolines <b>2e</b> and <b>2h</b>, and the pyridoquinoxalines <b>4h</b>, <b>4j</b> and <b>5n</b> (EC<sub>50</sub> range 1–5 μM). When tested in a replicon assay, compound <b>2h</b> was the sole derivative to also display anti-HCV activity (EC<sub>50</sub> = 3.1 μM). In enzyme assays, <b>1m</b>, <b>2h</b>, <b>5m</b> and <b>5n</b> proved to be potent inhibitors of the BVDV RNA-dependent RNA polymerase (RdRp), while only <b>2h</b> also inhibited the recombinant HCV enzyme

Topics: CHIM/09 Farmaceutico tecnologico applicativo, CHIM/08 Chimica farmaceutica
Publisher: Pergamon / Elsevier
Year: 2011
DOI identifier: 10.1016/j.bmc.2011.10.009
OAI identifier:
Provided by: UnissResearch
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