Studies on the anti-hepatitis C virus activity of newly synthesized tropolone derivatives: Identification of NS3 helicase inhibitors that specifically inhibit subgenomic HCV replication

Abstract: We synthesized new tropolone derivatives substituted with cyclic amines: piperidine, piperazine or pyrrolidine. The most active anti-helicase compound (IC50 =3.4μM), 3,5,7-tri[(4′-methylpiperazin-1′-yl)methyl]tropolone (2), inhibited RNA replication by 50% at 46.9μM (EC50) and exhibited the lowest cytotoxicity (CC50) >1mM resulting in a selectivity index (SI=CC50/EC50) >21. The most efficient replication inhibitor, 3,5,7-tri[(4′-methylpiperidin-1′-yl)methyl]tropolone (6), inhibited RNA replication with an EC50 of 32.0μM and a SI value of 17.4, whereas 3,5,7-tri[(3′-methylpiperidin-1′-yl)methyl]tropolone (7) exhibited a slightly lower activity with an EC50 of 35.6μM and a SI of 9.8. [Copyright &y& Elsevier]