title: 3-Biphenylimidazo[1,2-a]pyridines or [1,2-b]pyridazines and analogues, novel Flaviviridae inhibitors.
abstract: Using Ttou 84 as starting point, a novel class of biphenyl derivatives of imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine was designed to optimize the inhibitory properties on the replication of the bovine viral diarrhoea virus (BVDV) and hepatitis C virus (HCV). Three sites of pharmacomodulation were chosen i.e. positions 2, 3 and 6 on the central heterocyclic core structure. From the 49 analogues tested, only compound 18j (3-(2'-hydroxybiphen-3-yl)-2-(2-methoxyphenyl)-6-(thien-3-yl)imidazo[1,2-b]pyridazine) showed antiviral activity in the HCV replicon system reminiscent of selective inhibition (60-70% inhibition). Compound 4f (3-(biphen-3-yl)-2-(4-fluorophenyl)-6-phenylthioimidazo[1,2-a]pyridine) proved to be the most selective inhibitor of BVDV replication and showed no or only marginal cross-resistance with known inhibitors of pestivirus replication. The cross-resistance profile of 4f might indicate that 4f does not interact with the same binding site as BPIP, VP32947, AG110 or LZ37. From 42 analogues tested against both viruses, QSAR studies were discussed in regard to BVDV antiviral activity.
authors.affiliation: Université François Rabelais, UMR INRA 1282 Infectiologie et Santé Publique, Recherche et Innovation en Chimie Médicinale, Faculté de Pharmacie, 31 avenue Monge, F-37200 Tours, France. cecile.enguehard-gueiffier@univ-tours.fr
authors.forename: Cécile
authors.initials: C
authors.lastname: Enguehard-Gueiffier
authors.forename: Simone
authors.initials: S
authors.lastname: Musiu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Henry
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Véron
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mavel
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.forename: Alain
authors.initials: A
authors.lastname: Gueiffier
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; D011724:Pyridazines; D011725:Pyridines