New pyridinone derivatives as potent HIV-1 nonnucleoside reverse transcriptase inhibitors
- J Med Chem. 2009 Jun 25;52(12):3636-43. doi: 10.1021/jm801438e.
- 1. Laboratoire de Chimie des Materiaux Organiques and Laboratoire de Chimie Moleculaire Structurale, Facultes Universitaires Notre-Dame de la Paix, B-5000 Namur, Belgium.
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.