title: Madurahydroxylactone derivatives as dual inhibitors of human immunodeficiency virus type 1 integrase and RNase H.
abstract: A series of 29 madurahydroxylactone derivatives was evaluated for dual inhibition of human immunodeficiency virus type 1 (HIV-1) integrase and RNase H. While most of the compounds exhibited similar potencies for both enzymes, two of the derivatives showed 10- to 100-fold-higher selectivity for each enzyme, suggesting that distinct pharmacophore models could be generated. This study exemplifies the common and divergent structural requirements for the inhibition of two structurally related HIV-1 enzymes and demonstrates the importance of systematically screening for both integrase and RNase H when developing novel inhibitors.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. marchand@nih.gov
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: John A
authors.initials: JA
authors.lastname: Beutler
authors.forename: Antony
authors.initials: A
authors.lastname: Wamiru
authors.forename: Scott
authors.initials: S
authors.lastname: Budihas
authors.forename: Ute
authors.initials: U
authors.lastname: Möllmann
authors.forename: Lothar
authors.initials: L
authors.lastname: Heinisch
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.forename: Stuart F
authors.initials: SF
authors.lastname: Le Grice
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019427:HIV Integrase / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D019428:HIV Integrase Inhibitors; D007783:Lactones; C465231:madurahydroxylactone; D019427:HIV Integrase; D016914:Ribonuclease H