title: Novel 2-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,3,4-oxadiazole and 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole derivatives as dengue virus inhibitors targeting NS5 polymerase.
abstract: Using a functional high-throughput screening (HTS) and subsequent SAR studies, we have discovered a novel series of non-nucleoside dengue viral polymerase inhibitors. We report the elaboration of SAR around hit compound 1 as well as the synthesis and antiviral evaluation of 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole and 5-phenyl-2-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole analogues derived from a rapid and easily accessible chemical pathway. A large number of compounds prepared by this method were shown to possess in vitro activity against the polymerase of dengue virus. The most potent inhibitors were tested against Dengue virus clinical isolates on infected cells model and exhibit submicromolar activity on the four dengue virus serotypes.
authors.affiliation: Aix-Marseille Université, AFMB, AD2P, UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France.
authors.forename: Fatiha
authors.initials: F
authors.lastname: Benmansour
authors.affiliation: Aix-Marseille Université, AFMB, AD2P, UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France.
authors.forename: Cécilia
authors.initials: C
authors.lastname: Eydoux
authors.affiliation: UMR190, Emergence des Pathologies Virales, Aix-Marseille University, IRD French Institute of Research for Development, EHESP French School of Public Health, 27 Boulevard Jean Moulin, Marseille 13005, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Querat
authors.affiliation: UMR190, Emergence des Pathologies Virales, Aix-Marseille University, IRD French Institute of Research for Development, EHESP French School of Public Health, 27 Boulevard Jean Moulin, Marseille 13005, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: de Lamballerie
authors.affiliation: Aix-Marseille Université, AFMB, AD2P, UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
authors.affiliation: Aix-Marseille Université, AFMB, AD2P, UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Alvarez
authors.affiliation: Aix-Marseille Université, AFMB, AD2P, UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Guillemot
authors.affiliation: Aix-Marseille Université, AFMB, AD2P, UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France; CNRS, AFMB UMR 7257, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France. Electronic address: karine.barral@inserm.fr.
authors.forename: Karine
authors.initials: K
authors.lastname: Barral
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003715:Dengue / Q000188:drug therapy* / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D010069:Oxadiazoles; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C583463:1,3,4-oxadiazole; D012324:RNA-Dependent RNA Polymerase
keywords: 2-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,3,4-oxadiazole; 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole; Antiviral activity; Dengue virus; NS5 RdRp inhibitors