Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Abstract

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

Synthesis and anti-HCV determinant motif identification in pyranone carboxamide scaffold

“…We observed that when A and B both were phenyl, the compound was highly active with EC 50 0.35 µM. 7 However, substitution on A shown a tendency to decrease the anti-HCV potential of compounds irrespective of whether B is phenyl/substituted phenyl/alkyl/ alkanol/alkyl ester/benzyl. 4-hydroxyamino-α-pyranone carboxamide scaffold I and the scaffold for present investigation (II).…”

“…5,6 Therefore, novel therapies are invited for safer and more efficient treatment. In our previous investigation, 7 we had evaluated anti-HCV activities of new analogs based on 4-hydroxyamino-α-pyranone carboxamide (I, Fig. 1) with various combinations of A (phenyl/ substituted phenyl) and B (phenyl/substituted phenyl/alkyl/alkanol/alkyl ester/ benzyl).…”

“…To achieve this amide linkage, α-pyranone-3-carboxylic acids (2a-h) were synthesized from ketene dithioacetals (1a-h) by reacting them with diethylmalonate (DEM) in presence of NaH. 7 Appropriate amines were coupled with 2a-h to get the key amide intermediates 3a-10m. The SMe group at 4-position of amides was substituted by the reaction of hydroxylamine/2-aminoethanol/piperidine/Omethyl hydroxylamine to get the final compounds (11a-18a).…”

Tandem One‐Pot Approach to N‐Substituted Lactones by Carbon–Carbon Coupling Followed by 5‐exo‐dig or 6‐endo‐dig Cyclization: DFT Studies and Cyclization Mode

“…The synthetic γ‐alkylidenebutenolide C displays an antibacterial activity with a minimum inhibitory concentration (MIC) value of 20 µ g/mL against Escherichia coli while γ‐alkylidenebutenolide D exhibits cytotoxic activity against Ec9706 cells . In addition, the α‐pyranone carboxamide E is reported as promising anti‐hepatitis C agent . These skeletal motifs also feature as intermediates for the synthesis of related heterocycles and complex natural products …”

3D perspective into MIA‐QSAR: A case for anti‐HCV agents

“…The molecular data set selected for this study consists of 42 compounds with anti‐HCV (hepatitis C virus) activity, synthesized and characterized by Konreddy et al. (). Hepatitis C virus is a single‐stranded RNA virus that belongs to the Flaviviridae family.…”