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Bioorg Med Chem Lett. 2019 Jul 15;29(14):1836-1841. doi: 10.1016/j.bmcl.2019.05.003. Epub 2019 May 6.

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

Author information

1
Institute for Natural Products Applications and Research Technologies, Norman, OK 73019-5251, United States; Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, Norman, OK 73019-5251, United States.
2
Departments of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
3
Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, Norman, OK 73019-5251, United States.
4
Department of Chemistry, Dartmouth College, Hanover New Hampshire, 03755, United States.
5
Biochemistry, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
6
Biochemistry, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States; The Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, United States.
7
Departments of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
8
Institute for Natural Products Applications and Research Technologies, Norman, OK 73019-5251, United States; Department of Chemistry & Biochemistry, Stephenson Life Sciences Research Center, Norman, OK 73019-5251, United States. Electronic address: adam.duerfeldt@ou.edu.

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.

KEYWORDS:

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

PMID:
31104993
PMCID:
PMC6594187
[Available on 2020-07-15]
DOI:
10.1016/j.bmcl.2019.05.003

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