探索 1-(4-硝基苯基)-3-芳基丙-2-烯-1-酮支架对单胺氧化酶 B 的选择性抑制作用

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-09-27 DOI:10.1021/acsmedchemlett.4c0024610.1021/acsmedchemlett.4c00246

Rita Meleddu, Antonella Fais*, Benedetta Era, Sonia Floris, Simona Distinto, Antonio Lupia, Filippo Cottiglia, Alessia Onali, Erica Sanna, Daniela Secci, Giulia Atzeni, Laura Demuru, Pierluigi Caboni, Donatella Valenti and Elias Maccioni*,

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摘要

为了鉴定新的人类单胺氧化酶 B 选择性抑制剂，我们合成了一个 1-(4-硝基苯基)-3-芳基丙-2-烯-1-酮衍生物的小型文库。评估了它们对 MAO-A 和 MAO-B 同工酶的抑制活性，以确定其效力和选择性。所有新合成的化合物都是 B 型异构体的纳摩尔级抑制剂，IC50 浓度在 120 到 2.2 nM 之间。相反，只有在微摩尔浓度下才能观察到它们对 A 同工酶的活性。我们的研究结果证明了一个假设，即 1,3-二芳基丙烯酮支架可能是设计高效和选择性 MAO-B 抑制剂的重要起点。

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Exploring the 1-(4-Nitrophenyl)-3-arylprop-2-en-1-one Scaffold for the Selective Inhibition of Monoamine Oxidase B

A small library of 1-(4-nitrophenyl)-3-arylprop-2-en-1-one derivatives was synthesized to identify new human monoamine oxidase B selective inhibitors. Their inhibitory activity toward MAO-A and MAO-B isoforms was evaluated to determine their potency and selectivity. All newly synthesized compounds were nanomolar inhibitors of the B isoform with IC₅₀ concentrations ranging from 120 to 2.2 nM. Conversely, their activity toward the A isozyme was only observed at micromolar concentrations. Our results bear out the hypothesis that the 1,3-diarylpropenone scaffold could represent a valuable starting point for designing efficient and selective MAO-B inhibitors.

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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.

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