B-ring modified aurones as promising allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
Following our recent report showing the potential of naturally occurring aurones (2-benzylidenebenzofuran-3(2H)-ones) as anti-hepatitis C virus (HCV) agents, efforts were continued in order to refine the structural requirements for the inhibitory effect on HCV RNA-dependent RNA polymerase (RdRp). In this study, we targeted the B-ring moiety of aurones with the aim to improve structural features associated with higher inhibition of the targeted polymerase. In vitro evaluation of the RdRp inhibitory activity of the 37 newly synthesized compounds pointed out that the replacement of the B-ring with an N-substituted indole moiety induced the highest inhibitory effect. Of these, compounds 31, 40 and 41 were found to be the most active (IC50 = 2.3-2.4 μM). Docking experiments performed with the most active compounds revealed that the allosteric thumb pocket I of RdRp is the binding pocket for aurone analogues.
Univ. Grenoble Alpes, DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
Amel
A
Meguellati
INSERM U955, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
Abdelhakim
A
Ahmed-Belkacem
Univ. Grenoble Alpes, DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
Wei
W
Yi
Univ. Grenoble Alpes, DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
Romain
R
Haudecoeur
Univ. Grenoble Alpes, DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
Marie
M
Crouillère
INSERM U955, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
Rozenn
R
Brillet
INSERM U955, Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
Jean-Michel
JM
Pawlotsky
Univ. Grenoble Alpes, DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France.
Ahcène
A
Boumendjel
Univ. Grenoble Alpes, DPM UMR 5063, 38041 Grenoble, France; CNRS, DPM UMR 5063, 38041 Grenoble, France. Electronic address: Marine.Peuchmaur@ujf-grenoble.fr.
Marine
M
Peuchmaur
D000494:Allosteric Regulation / Q000187:drug effects; D000998:Antiviral Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D011487:Protein Conformation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000998:Antiviral Agents; D001572:Benzofurans; D004791:Enzyme Inhibitors; C486837:aurone; D012324:RNA-Dependent RNA Polymerase
Aurones; Hepatitis C virus; RNA-dependent RNA polymerase