title: Synthesis and structure-activity analysis of diphenylpyrazolodiazene inhibitors of the HIV-1 Nef virulence factor.
abstract: HIV-1 Nef is a critical AIDS progression factor yet underexplored target for antiretroviral drug discovery. A recent high-throughput screen for pharmacological inhibitors of Nef-dependent Src-family kinase activation identified a diphenylpyrazolodiazene hit compound with submicromolar potency in HIV-1 replication assays against a broad range of primary Nef variants. This compound, known as 'B9', binds directly to Nef and inhibits its dimerization in cells as a possible mechanism of action. Here were synthesized a diverse set of B9 analogs and identified structural features essential to antiretroviral activity. Chemical modifications to each of the three rings present in the parent compound were identified that did not compromise antiviral action. These analogs will guide the development of next-generation compounds with appropriate pharmacological profiles for assessment of antiretroviral activity in vivo.
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA 15261, USA.
authors.forename: Prema C
authors.initials: PC
authors.lastname: Iyer
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA 15261, USA.
authors.forename: Jielu
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, Suite 523, 450 Technology Drive, Pittsburgh, PA 15219, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Emert-Sedlak
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Kerry K
authors.initials: KK
authors.lastname: Moore
authors.affiliation: University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA 15261, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, Suite 523, 450 Technology Drive, Pittsburgh, PA 15219, USA. Electronic address: tsmithga@pitt.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Smithgall
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA 15261, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D001391:Azo Compounds; D011720:Pyrazoles; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1
keywords: Antiretroviral drug discovery; HIV Nef; HIV-1; Nef inhibitors