3-Amino-2(5H)furanones as inhibitors of subgenomic hepatitis C virus RNA replication Daniela Iannazzo a, * , Anna Piperno a , Giovanni Romeo a , Roberto Romeo a , Ugo Chiacchio b , Antonio Rescifina b , Emanuela Balestrieri c , Beatrice Macchi c , Antonio Mastino d , Riccardo Cortese e a Dipartimento Farmaco-Chimico, Università di Messina, Via SS. Annunziata, Messina 98168, Italy b Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, Catania 95125, Italy c Dipartimento di Neuroscienze, Università di Roma ‘‘Tor Vergata”, Via Montpellier 1 and IRCSS S. Lucia, Roma 00133, Italy d Dipartimento di Scienze Microbiologiche, Genetiche e Molecolari, Università di Messina, Salita Sperone 31, Messina 98168, Italy e CeInge, Via Comunale Margherita 482, Napoli, Italy article info Article history: Received 8 May 2008 Revised 27 August 2008 Accepted 4 September 2008 Available online 7 September 2008 Keywords: DKA HCV Furanones 1,3-Dipolar cycloaddition Isoxazolidines abstract A new class of compounds able to block the replication of subgenomic HCV RNA in liver cells is described. 3-Amino-2(5H)furanones 4 may be regarded as diketoacid analogues and were obtained by basic rear- rangement of the isoxazolidine nucleus. Ó 2008 Published by Elsevier Ltd. 1. Introduction Hepatitis C Virus (HCV) infection constitutes a global health problem, which affects more than 170 million individuals. 1,2 The NS5B RNA-dependent RNA polymerase (NS5B RdRp) has shown to be the catalytic core of the HCV replication machinery. 3,4 This enzyme is not expressed in uninfected cells, and, due to its unique features, represents an attractive target for the development of safe antiviral drugs. 5–7 The catalytic activity of the enzyme is mediated, in the active site, by two magnesium ions, which serve to activate the 3’-OH of the elongating RNA and to position the incoming nucleotide-tri- phosphate for the nucleophilic attack. 8–11 Different classes of NS5B inhibitors have been disclosed and they can be divided by their mechanism of action into three major classes: non-nucleoside inhibitors acting at allosteric binding sites, nucleoside analogues, and pyrophosphate analogues. The allosteric inhibitors include a variety of heterocyclic systems, which have been shown to bind to three distinct sites on the polymerase. 6,7,12 The others two classes are active-site inhibitors: the first are modified chain-terminating nucleoside (substrate) analogues 13–15 and the second are pyrophosphate (product) analogues, 16,17 namely diketoacids (DKA) 1. Actually, only three scaffolds have been reported: phenyl-DKA 18 like 1, meconic acid derivatives 2 19 and carboxypyrimidines 3 20 (Fig. 1). In these last years, we have developed an efficient synthetic procedure towards the construction of 3-amino-2(5H)furanones by basic treatment of 3-alkoxycarbonyl substituted isoxazoli- dines. 21 We have assumed that the introduction of a carbonyl group at the C 4 position of the 3-amino-2(5H)furanone skeleton, as in compounds 4, could produce potential inhibitors of pyrophos- phate site. In fact, 3-amino-2(5H)furanones 4 may be regarded as DKA cyclic analogues: the 1,3-diketonic functionality is replaced 0968-0896/$ - see front matter Ó 2008 Published by Elsevier Ltd. doi:10.1016/j.bmc.2008.09.006 * Corresponding author. Tel.: +39 090356230; fax: +39 0906766562. E-mail address: UUdiannazzo@pharma.unime.itUU (D. Iannazzo). Figure 1. NS5B pyrophosphate analogues inhibitors and new potential ones. Bioorganic & Medicinal Chemistry 16 (2008) 9610–9615 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc