High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold I based on 4-hydroxyamino α-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure−activity relationship (SAR) was explored with several newly synthesized compounds. In all promising compounds (17−19, 21−22, 24− 25, and 49) with EC 50 ranging 0.15 to 0.40 μM, the aryl group at C-6 position of α-pyranone were unsubstituted. In particular, 25 demonstrated potential anti-HCV activity with EC 50 of 0.18 μM in cell based HCV replicon system with lower cytotoxicity (CC 50 > 20 μM) and provided a new scaffold for anti-HCV drug development. Further investigations, including biochemical characterization, are yet to be performed to elucidate its possible mode of action. KEYWORDS: Hepatitis C virus, non-nucleoside inhibitor, α-pyranone carboxamide H epatitis C virus (HCV) is a single stranded 9.6 kb RNA virus of the Flaviviridae family predominantly infecting hepatocytes. HCV infection is silent and in long-term may lead to serious liver disease, including fibrosis and cirrhosis followed by hepatocellular carcinoma. 1,2 The prophylactic treatment has been of very limited success, 3 and so far no vaccine is available. 4 A serious health threat has been realized, and a series of investigations are underway to discover direct acting antivirals (DAAs) as promising anti-HCV agents. 5 The potential molecules 1−4 (Figure 1) belonging to DAAs target mainly three viral enzymes: (i) protease NS3/4A, (ii) replicase factor NS5A, and (iii) HCV RNA-dependent RNA polymerase (HCV RdRp) NS5B. 6 The medicinal chemistry approaches with breakthrough exploration in HCV biology 7 were translated recently into first generation DAAs, boceprevir 8 and telaprevir 9 (protease inhibitors) approved by US FDA. Several new generation protease inhibitors are under serious investigations to combat the challenges associated with anti-HCV therapy. 10,11 The current standard of care (SoC) for HCV treatment includes one of the approved protease inhibitors combined with pegylated interferon-α (PegIFN) and ribavirin (RBV).The new regimen improves sustained viral response (SVR) rates to ∼75%; 8,9 however, it also adds side effect burden to patients. The use of PegIFN/RBV is associated with severe side effects followed by treatment discontinuation and contraindication. 12 Overall, drug-resistance, drug−drug interactions, and side effects are major concerns, 13 which demand effective PegIFN/RBV free regimen. In addition to recent success in protease inhibitors, 10,11 parallel research efforts are in progress to discover nucleoside inhibitors (NIs) to find novel DAAs to target HCV RdRp. 14,15 Similarly, several non-nucleoside allosteric inhibitors are in development phase, which may provide a choice of combination with other DAAs to discover
A series of 7-deazaneplanocin A (7-DNPA, 2) analogues were synthesized and evaluated for in vitro antiviral activity against HBV and HCV. The synthesis of target carbocyclic nucleosides were accomplished via a convergent procedure. 7-Substitutions were introduced by using 7-substituted-7-deaza heterocyclic base precursors (F, Cl, Br, and I) or via substitution reactions after the synthesis of the carbocyclic nucleosides. Among the synthesized compounds, 2, 13–15, 24 and 27 exhibited significant anti-HCV activity (EC50 ranged from 1.8 to 20.1 µM), and compounds 2, 15, 22 and 24 demonstrated moderate to potent anti-HBV activity (EC50 0.3 to 3.3 µM). In addition, the compound 24 also showed the activity against lamivudine- and adefovir- associated HBV mutants.
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