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

In this study 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 cytotoxicity and antiviral activity against RNA viruses representative of the three genera of the Flaviviridae family, that is BVDV (Pestivirus), YFV (Flavivirus) and HCV (Hepacivirus). Quinoline derivatives were also tested against representatives of other RNA virus families containing single-stranded, either positive-sense (ssRNA +) or negative-sense (RNA -), 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 1m, the imidazoquinolines 2e and 2h, and the pyridoquinoxalines 4h, 4j and 5n (EC 50 range 1-5 μM). When tested in a replicon assay, compound 2h was the sole derivative to also display anti-HCV activity (EC 50 = 3.1 μM). In enzyme assays, 1m, 2h, 5m and 5n proved to be potent inhibitors of the BVDV RNA-dependent RNA polymerase (RdRp), while only 2h also inhibited the recombinant HCV enzyme.