Discovery of Naturally Occurring Aurones That Are Potent Allosteric Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase

Abstract

We have identified naturally occurring 2-benzylidenebenzofuran-3-ones (aurones) as new templates for non-nucleoside hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors. The aurone target site, identified by site-directed mutagenesis, is located in thumb pocket I of HCV RdRp. The RdRp inhibitory activity of 42 aurones was rationally explored in an enzyme assay. Molecular docking studies were used to determine how aurones bind to HCV RdRp and to predict their range of inhibitory activity. Seven aurone derivatives were found to have potent inhibitory effects on HCV RdRp, with IC(50) below 5 μM and excellent selectivity index (inhibition activity versus cellular cytotoxicity). The most active aurone analogue was (Z)-2-((1-butyl-1H-indol-3-yl)methylene)-4,6-dihydroxybenzofuran-3(2H)-one (compound 51), with an IC(50) of 2.2 μM. Their potent RdRp inhibitory activity and their low toxicity make these molecules attractive candidates as direct-acting anti-HCV agents.

Synthesis and anti-cancer activity evaluation of new aurone derivatives

“…Aurones, (Z)-2-benzylidenebenzofuran-3-(2H)-ones ( Figure 1c), constitute a less studied subclass of flavonoids although they are isosteres of flavones 5,6 . However, they have attracted attention with promising biological potential such as anti-microbial 7 , anti-cancer 8 , anti-leishmanial [9][10][11] , anti-histaminic 12 , antiinflammatory 13 , antioxidant 14 , insect anti-feedant 15 , herbicidal 16 , anti-HIV 17,18 , anti-HCV (hepatis C virus) 19,20 , anti-malarial 21,22 , ChE inhibitory 23,24 , MAO inhibitory 25 activities in the specified studies. The observed biological potential is thought to be due to the similarity of adenine of ATP and the flavonoids, consequently inhibition of the activity of ATP-dependent enzymes and proteins, which is essential for the function of enzymes and receptors.…”

Synthesis of the Proposed Structure of Damaurone D and Evaluation of Its Anti-inflammatory Activity

“…The reaction mixture was diluted with EtOAc and 2 N HCl solution. The organic layer was washed with water and brine, dried over MgSO 4 and concentrated in vacuo. Purification of the residue via flash column chromatography on silica gel (EtOAc-n-CH 2 Cl 2 -hexane=1 : 1 : 20 …”

“…To the reaction mixture was added 1 M sodium hydroxide (NaOH) solution (10 mL) at ambient temperature and stirred for 1 h. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with water and brine, dried over MgSO 4 and concentrated in vacuo. Purification of the residue via flash column chromatography on silica gel (EtOAc-n-hexane-CH 2 Cl 2 =1 : 1 : 10) afforded 253 mg (64%) of the benzofuranone 2 as pale yellow solid with a melting point of 148-150°C, and trace amount of the bromoacetophenone 9: FT-IR (thin film, neat) ν max 2974,1974 Treatment of Compounds Raw264.7 Macrophages were pretreatment with damaurone D (1) or butein at different concentrations for 1 h and then treatment with LPS 10 ng/mL for 24 h in 12-well cell culture plate.…”

“…2) In this regard, these aurones and their derivatives have been considered as attractive targets in terms of both synthetic 3) and medicinal chemistry. 4,5) Recently, damaurone D (1), an isoprenylated aurone, was isolated by Lei et al from Rosa damascena, a plant that belongs to genus Rosa. 6) The genus Rosa including Rosa damascena has not only been used for gardening and cosmetics, but also as a traditional medication to treat depression, inflammation, and infectious diseases.…”

Recent advances on the synthesis of hepatitis C virus NS5B RNA-dependent RNA-polymerase inhibitors

“…236 reacted with aromatic aldehyde 237 by the aldol condensation to afford 238, which then was converted to the aurone derivative bearing a hydroxyl group at the N-substituted indole moiety 239 by the demethylation using boron tribromide [95]. In this route, although its overall yield was high, most of intermediates needed to be purified by column chromatography on silica gel.…”