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DOI: 10.1055/a-2586-6260
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Small Molecules in Medicinal Chemistry

Efficient Regioselective Synthesis of Benzimidazoles and Azabenz­imidazoles to Enable the Rapid Development of Structure–Activity Relationships for Activation of SLACK Potassium Channels

Paul K. Peprah
a   Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
b   College of Biomedical and Translational Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
,
Brittany D. Spitznagel
c   Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
,
Yu Du
c   Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
d   Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA
,
Dalena Nguyen
a   Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
,
C. David Weaver
c   Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
d   Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA
,
Kyle A. Emmitte  ∗
a   Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
› Author Affiliations
This research was funded by the National Institute of Mental Health (grant number R21MH125257) (C.D.W. and K.A.E.). Funding for the WaveFront Biosciences Panoptic platform was provided by the Office of The Director (OD) of the National Institutes of Health (award number 1S10OD021734). This instrument is housed and maintained in the Vanderbilt Institute of Chemical Biology’s High-throughput Screening Center.
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Abstract

The sodium-activated potassium channel known as SLACK (KNa1.1 or Slo2.2) is widely expressed in the central nervous system and represents a potential target for the treatment of several neurological disorders. While much recent progress has been made toward the discovery of small-molecule inhibitors of these channels, reports regarding small-molecule activators have been scant. Having identified such compounds via a high-throughput screen, we were interested in establishing structure–activity relationships that could serve as the foundation for the design of potent activators of SLACK channels. In this letter, we describe the implementation of an efficient synthetic approach to the regioselective synthesis of a series of benzimidazole and azabenzimidazoles based on one of our hit compounds. The key step utilizes a one-pot reduction/formylation/condensation reaction of 2-nitro-arylamines. Also presented herein are the functional activities for 15 new analogues prepared by this approach and obtained via a thallium-flux assay in cells stably expressing human wild-type SLACK channels. Many of these new analogues demonstrate substantially improved potency relative to the initial hit compound and provide valuable new data that can be utilized in the design of additional derivatives.

Key words

SLACK - KNa1.1 - Slo2.2 - potassium channel - benzimidazoles

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2586-6260.
  • Supporting Information


Publication History

Received: 28 February 2025

Accepted after revision: 10 April 2025

Accepted Manuscript online:
14 April 2025

Article published online:
23 May 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

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