Synthesis and structure-activity analysis of diphenylpyrazolodiazene inhibitors of the HIV-1 Nef virulence factor

Prema C Iyer; Jielu Zhao; Lori A Emert-Sedlak; Kerry K Moore; Thomas E Smithgall; Billy W Day

doi:10.1016/j.bmcl.2014.02.045

Synthesis and structure-activity analysis of diphenylpyrazolodiazene inhibitors of the HIV-1 Nef virulence factor

Bioorg Med Chem Lett. 2014 Apr 1;24(7):1702-6. doi: 10.1016/j.bmcl.2014.02.045. Epub 2014 Feb 26.

Authors

Prema C Iyer¹, Jielu Zhao¹, Lori A Emert-Sedlak², Kerry K Moore³, Thomas E Smithgall⁴, Billy W Day⁵

Affiliations

¹ Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA; University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA 15261, USA.
² Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Bridgeside Point II, Suite 523, 450 Technology Drive, Pittsburgh, PA 15219, USA.
³ Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁴ 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.
⁵ 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.

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.

Keywords: Antiretroviral drug discovery; HIV Nef; HIV-1; Nef inhibitors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Azo Compounds / chemical synthesis
Azo Compounds / chemistry
Azo Compounds / pharmacology*
Cell Line
Dose-Response Relationship, Drug
HIV Infections / drug therapy*
HIV Infections / virology
HIV-1 / drug effects*
HIV-1 / genetics
Humans
Microbial Sensitivity Tests
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
nef Gene Products, Human Immunodeficiency Virus / drug effects*
nef Gene Products, Human Immunodeficiency Virus / genetics

Substances

Anti-HIV Agents
Azo Compounds
Pyrazoles
nef Gene Products, Human Immunodeficiency Virus
nef protein, Human immunodeficiency virus 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding