title: Coumarin-based inhibitors of HIV integrase.
abstract: The structures of a large number of HIV-1 integrase inhibitors have in common two aryl units separated by a central linker. Frequently at least one of these aryl moieties must contain 1,2-dihydroxy substituents in order to exhibit high inhibitory potency. The ability of o-dihydroxy-containing species to undergo in situ oxidation to reactive quinones presents a potential limitation to the utility of such compounds. The recent report of tetrameric 4-hydroxycoumarin-derived inhibitor 5 provided a lead example of an inhibitor which does not contain the catechol moiety. Compound 5 represents a large, highly complex yet symmetrical molecule. It was the purpose of the present study to determine the critical components of 5 and if possible to simplify its structure while maintaining potency. In the present study, dissection of tetrameric 5 (IC50 = 1.5 microM) into its constituent parts showed that the minimum active pharmacophore consisted of a coumarin dimer containing an aryl substituent on the central linker methylene. However, in the simplest case in which the central linker aryl unit consisted of a phenyl ring (compound 8, IC50 = 43 microM), a significant reduction in potency resulted by removing two of the original four coumarin units. Replacement of this central phenyl ring by more extended aromatic systems having higher lipophilicity improved potency, as did the addition of 7-hydroxy substituents to the coumarin rings. Combining these latter two modifications resulted in compounds such as 3,3'-(2-naphthalenomethylene)bis[4,7-dihydroxycoumarin] (34, IC50 = 4.2 microM) which exhibited nearly the full potency of the parent tetramer 5 yet were structurally much simpler.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: N
authors.initials: N
authors.lastname: Neamati
authors.forename: H
authors.initials: H
authors.lastname: Hong
authors.forename: A
authors.initials: A
authors.lastname: Mazumder
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Sunder
authors.forename: G W
authors.initials: GW
authors.lastname: Milne
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
authors.forename: T R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007536:Isomerism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D003374:Coumarins; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D019428:HIV Integrase Inhibitors