Briguglio, Irene (2011) Sintesi e valutazione di sistemi azotati triciclici aromatici come possibili agenti antivirali. Doctoral Thesis.
In this PhD project three new classes of linear N-tricyclic compounds, derived by condensation of the quinoline nucleus with 1,2,3-triazole, imidazole or pyrazine, were synthesized, obtaining triazolo[4,5-g]quinolines, imidazo[4,5-g]quinolines and pyrido[2,3-g]quinoxalines, respectively. Title compounds were tested in cell-based assays for citotoxicity and antiviral activity against RNA viruses representative of the three genera of the Flaviviridae family: BVDV (Pestivirus), YFV (Flavivirus) and HCV (Hepacivirus). Quinoline derivatives were also tested against representatives of other RNA virus families containing single-stranded, either positive (ssRNA+) or negative (ssRNA-) sense, and double-stranded genomes (dsRNA), as well as against representatives of two DNA virus families. Derivatives belonging to all classes showed activity against BVDV. Among the most potent was the imidazoquinolines 1α (EC50=0.3 μM) and 1β (EC50=1.2 microM), the bis-triazoloquinoline 14 (EC50=1 μM), and the pyridoquinoxalines 25, 26 and 28 (EC50 range 2.6–5 μM). When tested in a replicon assay, only compounds 1α and 1β displayed a good anti-HCV activity, whereas derivative 1β resulted the most potent (EC50=3.1 μM). Furthermore, in enzyme assays, 1β, 14 and 25 proved to be potent inhibitors of the BVDV RNA-dependent RNA polymerase (RdRp), while only 1β also inhibited the recombinant HCV enzyme. Finally, some tested quinolines showed moderate, although selective activity against CVB-5, Reo-1 and RSV.
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