First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors

Yangxiong Li, Jessi J. Gardner, Katherine R. Fortney, Inga V. Leus, Vincent Bonifay, Helen I. Zgurskaya, Alexandre A. Pletnev, Sheng Zhang, Zhong-Yin Zhang, Gordon W. Gribble, Stanley Spinola, Adam S. Duerfeldt

Research output: Contribution to journalArticle

Abstract

Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StatePublished - Jan 1 2019

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Structure-Activity Relationship
Phosphoric Monoester Hydrolases
Amines
Indoles
Scaffolds
Lead compounds
Derivatives
Virulence
Permeability
Signal Transduction
Signal transduction
Stereochemistry
Pathogens
Escherichia coli
Amino Acids
Permeation
Membranes
Substitution reactions
Infection
Chemical activation

Keywords

  • Antibacterial
  • CpxRA
  • Drug discovery
  • Efflux
  • Medicinal chemistry
  • Permeability
  • Sensory kinase
  • Two-component system

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors. / Li, Yangxiong; Gardner, Jessi J.; Fortney, Katherine R.; Leus, Inga V.; Bonifay, Vincent; Zgurskaya, Helen I.; Pletnev, Alexandre A.; Zhang, Sheng; Zhang, Zhong-Yin; Gribble, Gordon W.; Spinola, Stanley; Duerfeldt, Adam S.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2019.

Research output: Contribution to journalArticle

Li, Yangxiong ; Gardner, Jessi J. ; Fortney, Katherine R. ; Leus, Inga V. ; Bonifay, Vincent ; Zgurskaya, Helen I. ; Pletnev, Alexandre A. ; Zhang, Sheng ; Zhang, Zhong-Yin ; Gribble, Gordon W. ; Spinola, Stanley ; Duerfeldt, Adam S. / First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2019.
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AU - Gardner, Jessi J.

AU - Fortney, Katherine R.

AU - Leus, Inga V.

AU - Bonifay, Vincent

AU - Zgurskaya, Helen I.

AU - Pletnev, Alexandre A.

AU - Zhang, Sheng

AU - Zhang, Zhong-Yin

AU - Gribble, Gordon W.

AU - Spinola, Stanley

AU - Duerfeldt, Adam S.

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N2 - Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.

AB - Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.

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