作为丙酮酸羧化酶抑制剂的 1,3-二取代咪唑烷-2,4,5-三酮的合成与评估

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-06-26 DOI:10.1021/acsmedchemlett.4c00183

Nicholas O. Schneider, Kendra Gilreath, Niel M. Henriksen, William A. Donaldson, Subhabrata Chaudhury* and Martin St. Maurice*,

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引用次数: 0

摘要

通过硅学筛选方法，人们发现取代的咪唑烷三酮（IZTs）是丙酮酸羧化酶（PC）的强效抑制剂。2-(2,4,5-三氧代-3-取代咪唑烷-1-基)乙酸烷基酯（6i-6r）是该系列中最有效的抑制剂，其 IC50 值介于 3 和 12 μM 之间，并且几种 IZT 在人工膜上表现出很高的被动渗透性。IZT 对丙酮酸是混合型抑制剂，对 ATP 则是非竞争性抑制剂。这类抑制剂似乎对 PC 具有选择性。IZT 系列抑制剂不抑制金属酶人类碳酸酐酶 II 和基质金属蛋白酶-12，也不抑制相关的生物素依赖性酶胍羧化酶。总之，IZT 有望成为 PC 抑制剂，在细胞和体内系统中具有潜在的下游应用前景。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

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

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.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.