title: Competitive inhibition of HIV-1 protease by 4-hydroxy-benzopyran-2-ones and by 4-hydroxy-6-phenylpyran-2-ones.
abstract: The nonpeptide compounds C1 (4-hydroxy-3-(3-phenoxypropyl)-1-benzopyran-2-one) and P1 (4-hydroxy-6-phenyl-3-(phenylthio)pyran-2-one) are structurally novel low micromolar inhibitors of the protease of human immunodeficiency virus type 1 (HIV-1). Kinetic analysis revealed that both compounds are competitive inhibitors, with Ki values of 1.0 microM (C1) and 1.1 microM (P1), that act in a reversible fast-binding manner. Structural analogs of both compounds indicate that the pyran-2-one group, the 4-hydroxyl group and substitution at the 3 position are all necessary for inhibitory activity. These two pyranones provide excellent initial compounds in the development of therapeutically effective HIV-1 protease inhibitors, since they are small achiral nonpeptide molecules more easily synthesized and with potentially better pharmacological characteristics than peptide inhibitors of the protease.
authors.affiliation: Department of Biochemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: P J
authors.initials: PJ
authors.lastname: Tummino
authors.forename: D
authors.initials: D
authors.lastname: Ferguson
authors.forename: L
authors.initials: L
authors.lastname: Hupe
authors.forename: D
authors.initials: D
authors.lastname: Hupe
mesh_terms: D000595:Amino Acid Sequence; D001578:Benzopyrans; D001667:Binding, Competitive; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000201:enzymology*; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D017320:HIV Protease Inhibitors; D010455:Peptides