title: New pyridinone derivatives as potent HIV-1 nonnucleoside reverse transcriptase inhibitors.
abstract: Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (10) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC(50). Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (22) or 3-isopropyl group (23) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains.
authors.affiliation: Laboratoire de Chimie des Materiaux Organiques and Laboratoire de Chimie Moleculaire Structurale, Facultes Universitaires Notre-Dame de la Paix, B-5000 Namur, Belgium.
authors.forename: Kiet
authors.initials: K
authors.lastname: Le Van
authors.forename: Christine
authors.initials: C
authors.lastname: Cauvin
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Walque
authors.forename: Benoît
authors.initials: B
authors.lastname: Georges
authors.forename: Sandro
authors.initials: S
authors.lastname: Boland
authors.forename: Valérie
authors.initials: V
authors.lastname: Martinelli
authors.forename: Dominique
authors.initials: D
authors.lastname: Demonté
authors.forename: François
authors.initials: F
authors.lastname: Durant
authors.forename: László
authors.initials: L
authors.lastname: Hevesi
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006678:HIV / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase