Synthesis and Evaluation of 1,3-Disubstituted Imidazolidine-2,4,5-triones as Inhibitors of Pyruvate Carboxylase.

Autor: Schneider NO; Department of Biological Science, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881, United States., Gilreath K; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881, United States., Henriksen NM; Atomwise, Inc., 250 Sutter St, Suite 650, San Francisco, California 94108, United States., Donaldson WA; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881, United States., Chaudhury S; Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881, United States., St Maurice M; Department of Biological Science, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Jun 26; Vol. 15 (7), pp. 1088-1093. Date of Electronic Publication: 2024 Jun 26 (Print Publication: 2024).
DOI: 10.1021/acsmedchemlett.4c00183
Abstrakt: 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 IC 50 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.
Competing Interests: The authors declare no competing financial interest.
(© 2024 American Chemical Society.)
Databáze: MEDLINE
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