Document Type
Article
Publication Date
2024
Publisher
American Chemical Society
Source Publication
ACS Medicinal Chemistry Letters
Source ISSN
1948-5875
Original Item ID
DOI: 10.1021/acsmedchemlett.4c00183
Abstract
Substituted imidazolidinetriones (IZTs) have been identified as potent inhibitors of pyruvate carboxylase (PC) through an in silico screening approach. Alkyl 2-(2,4,5-trioxo-3-substituted imidazolidin-1-yl)acetates (6i–6r) are the most potent of the series, with IC50 values between 3 and 12 μM, and several IZTs demonstrate high passive permeability across an artificial membrane. IZTs are mixed-type inhibitors with respect to pyruvate and noncompetitive with respect to ATP. This class of inhibitors appears to be selective for PC. Inhibitors in the IZT series do not inhibit the metalloenzymes human carbonic anhydrase II and matrix metalloprotease-12, and they do not inhibit the related biotin-dependent enzyme, guanidine carboxylase. Altogether, IZTs offer promise as PC inhibitors with potential downstream applications in cellular and in vivo systems.
Recommended Citation
Schneider, Nicholas O.; Gilreath, Keandra; Henriksen, Niel M.; Donaldson, William A.; Chaudhury, Subhabrata; and St. Maurice, Martin, "Synthesis and Evaluation of 1,3-Disubstituted Imidazolidine-2,4,5-triones as Inhibitors of Pyruvate Carboxylase" (2024). Biological Sciences Faculty Research and Publications. 995.
https://epublications.marquette.edu/bio_fac/995
Comments
Accepted version. ACS Medicinal Chemistry Letters, Vol. 15, No. 7 (2024): 1088-1093. DOI. © 2024 American Chemical Society. Used with permission.