Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3β Inhibitors

Schneider, Nicholas O.; Gilreath, Kendra; Burkett, Daniel J.; St. Maurice, Martin; Donaldson, William A.

doi:10.3390/ph17050570

Open AccessArticle

Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3β Inhibitors

by

Nicholas O. Schneider

¹,

Kendra Gilreath

²,

Daniel J. Burkett

²,

Martin St. Maurice

¹ and

William A. Donaldson

^2,*

¹

Department of Biological Sciences, Marquette University, P.O. Box 1881, Milwaukee, WI 53201, USA

²

Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201, USA

^*

Author to whom correspondence should be addressed.

Pharmaceuticals 2024, 17(5), 570; https://doi.org/10.3390/ph17050570

Submission received: 13 March 2024 / Revised: 21 April 2024 / Accepted: 23 April 2024 / Published: 29 April 2024

(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry 2023)

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Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3β. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17–29) were prepared and evaluated for the inhibition of GSK-3β at 25 μM. The IC₅₀ values of five of these compounds was determined; the two best inhibitors are 5-[(4′-chloro-2-pyridinyl)methylene]hydantoin (IC₅₀ = 2.14 ± 0.18 μM) and 5-[(6′-bromo-2-pyridinyl)methylene]hydantoin (IC₅₀ = 3.39 ± 0.16 μM). The computational docking of the compounds with GSK-3β (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 μM and against human carbonic anhydrase at 200 μM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 μM.

Keywords: nitrogen heterocycles; glycogen synthase kinase 3β; computational docking

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MDPI and ACS Style

Schneider, N.O.; Gilreath, K.; Burkett, D.J.; St. Maurice, M.; Donaldson, W.A. Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3β Inhibitors. Pharmaceuticals 2024, 17, 570. https://doi.org/10.3390/ph17050570

AMA Style

Schneider NO, Gilreath K, Burkett DJ, St. Maurice M, Donaldson WA. Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3β Inhibitors. Pharmaceuticals. 2024; 17(5):570. https://doi.org/10.3390/ph17050570

Chicago/Turabian Style

Schneider, Nicholas O., Kendra Gilreath, Daniel J. Burkett, Martin St. Maurice, and William A. Donaldson. 2024. "Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3β Inhibitors" Pharmaceuticals 17, no. 5: 570. https://doi.org/10.3390/ph17050570

APA Style

Schneider, N. O., Gilreath, K., Burkett, D. J., St. Maurice, M., & Donaldson, W. A. (2024). Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3β Inhibitors. Pharmaceuticals, 17(5), 570. https://doi.org/10.3390/ph17050570

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Synthesis and Evaluation of 5-(Heteroarylmethylene)hydantoins as Glycogen Synthase Kinase-3β Inhibitors

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