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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

Carta, Antonio and Briguglio, Irene and Piras, Sandra and Corona, Paola and Boatto, Gianpiero and Nieddu, Maria and Giunchedi, Paolo and Marongiu, Maria Elena and Giliberti, Gabriele and Iuliano, Filippo and Blois, Sylvain and Ibba, Cristina and Busonera, Bernardetta and La Colla, Paolo (2011) Quinoline tricyclic derivatives: design, synthesis and evaluation of the antiviral activity of three new classes of RNA-dependent RNA polymerase inhibitors. Bioorganic & Medicinal Chemistry, Vol. 19 (23), p. 7070-7084. eISSN 1464-3391. Article.

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DOI: 10.1016/j.bmc.2011.10.009

Abstract

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 (EC50 range 1–5 μM). When tested in a replicon assay, compound 2h was the sole derivative to also display anti-HCV activity (EC50 = 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.

Item Type:Article
ID Code:7323
Status:Published
Refereed:Yes
Uncontrolled Keywords:Triazolo[4,5-g]quinolines, Imidazo[4,5-g]quinolines, Pyrido[2,3-g]quinoxalines, HCV, Flaviviridae
Subjects:Area 03 - Scienze chimiche > CHIM/09 Farmaceutico tecnologico applicativo
Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze del farmaco
Publisher:Pergamon / Elsevier
eISSN:1464-3391
Deposited On:04 Apr 2012 10:35

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