title: Synthesis, biological activity and structure-activity relationship of 4,5-dimethoxybenzene derivatives inhibitor of rhinovirus 14 infection.
abstract: Human rhinoviruses are a common cause of respiratory infections, and thus constitute an important target for medicinal chemistry. Still, no drug has been approved for clinical use. We report herein the discovery of dibenzenic derivatives with potent and specific in vitro anti-rhinoviral 14 activity. A total of 99 structural analogues were synthesized by an original synthesis method, i.e. through one organic agent Tetrakis(DimethylAmino)Ethylene (TDAE) and a structure-activity relationship was established. It was shown that 4,5-dimethoxy scaffold and the presence of a C-4 substituted aromatic moiety were necessary to the in vitro activity of these original agents. However, modifications on liker were not convincing. The benzonitrile derivative 23 was identified as the most potent and selective inhibitor of rhinovirus replication in these series (EC₅₀ of 2 ± 0.5 μM, CC₅₀ of 184 μM, selectivity index of 92).
authors.affiliation: Aix-Marseille Univ, Institut de Chimie Radicalaire, UMR 7273, CNRS 27, Boulevard Jean Moulin Marseille, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Roche
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Céline
authors.initials: C
authors.lastname: Lacroix
authors.affiliation: Aix-Marseille Univ, Institut de Chimie Radicalaire, UMR 7273, CNRS 27, Boulevard Jean Moulin Marseille, France.
authors.forename: Omar
authors.initials: O
authors.lastname: Khoumeri
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Franco
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium. Electronic address: johan.neyts@rega.kuleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Aix-Marseille Univ, Institut de Chimie Radicalaire, UMR 7273, CNRS 27, Boulevard Jean Moulin Marseille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Terme
authors.affiliation: Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: Aix-Marseille Univ, Institut de Chimie Radicalaire, UMR 7273, CNRS 27, Boulevard Jean Moulin Marseille, France. Electronic address: patrice.vanelle@univ-amu.fr.
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D010850:Picornaviridae Infections / Q000188:drug therapy*; D012229:Rhinovirus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C000593214:4-(2-(4,5-dimethoxy-2-nitrophenyl)-1-hydroxyethyl)benzonitrile; D000998:Antiviral Agents; D009570:Nitriles; D010626:Phenylethyl Alcohol
keywords: 4,5-Dimethoxybenzenes; Antiviral activity; Human rhinovirus 14; Tetrakis(DimethylAmino)Ethylene