title: Structure-activity analysis of vinylogous urea inhibitors of human immunodeficiency virus-encoded ribonuclease H.
abstract: Vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (compounds 1 and 2, respectively) were recently identified to be modestly potent inhibitors of the RNase H activity of HIV-1 and HIV-2 reverse transcriptase (RT). Both compounds shared a 3-CONH(2)-substituted thiophene ring but were otherwise structurally unrelated, which prevented a precise definition of the pharmacophore. We have therefore examined a larger series of vinylogous ureas carrying amide, amine, and cycloalkane modifications of the thiophene ring of compound 1. While cycloheptane- and cyclohexane-substituted derivatives retained potency, cyclopentane and cyclooctane substitutions eliminated activity. In the presence of a cycloheptane ring, modifying the 2-NH(2) or 3-CONH(2) functions decreased the potency. With respect to compound 2, vinylogous ureas whose dimethylthiophene ring contained modifications of the 2-NH(2) and 3-CONH(2) functions were investigated. 2-NH(2)-modified analogs displayed potency equivalent to or enhanced over that of compound 2, the most active of which, compound 16, reflected intramolecular cyclization of the 2-NH(2) and 3-CONH(2) groups. Molecular modeling was used to define an inhibitor binding site in the p51 thumb subdomain, suggesting that an interaction with the catalytically conserved His539 of the p66 RNase H domain could underlie inhibition of RNase H activity. Collectively, our data indicate that multiple functional groups of vinylogous ureas contribute to their potencies as RNase H inhibitors. Finally, single-molecule spectroscopy indicates that vinylogous ureas have the property of altering the reverse transcriptase orientation on a model RNA-DNA hybrid mimicking initiation plus-strand DNA synthesis.
authors.affiliation: RT Biochemistry Section, HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
authors.forename: Suhman
authors.initials: S
authors.lastname: Chung
authors.forename: Michaela
authors.initials: M
authors.lastname: Wendeler
authors.forename: Jason W
authors.initials: JW
authors.lastname: Rausch
authors.forename: Greg
authors.initials: G
authors.lastname: Beilhartz
authors.forename: Matthias
authors.initials: M
authors.lastname: Gotte
authors.forename: Barry R
authors.initials: BR
authors.lastname: O'Keefe
authors.forename: Alun
authors.initials: A
authors.lastname: Bermingham
authors.forename: John A
authors.initials: JA
authors.lastname: Beutler
authors.forename: Shixin
authors.initials: S
authors.lastname: Liu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhuang
authors.forename: Stuart F J
authors.initials: SF
authors.lastname: Le Grice
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D054309:Ribonuclease H, Human Immunodeficiency Virus