Decoupling Neuroprotection from MAO Inhibition via Indane-to-Azaindane Bioisosteric Replacement of Rasagiline

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-12 DOI:10.1021/acsmedchemlett.6c00407

Ivo E. Sampaio-Dias, Sara C. Silva-Reis, Xavier C. Correia, Hugo F. Costa-Almeida, Maria B. Igreja-Cardoso, Gabriel M. Azevedo, Vera M. Costa, Damijan Knez, Stanislav Gobec, José E. Rodríguez-Borges

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Abstract

Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with neuroprotective effects, whose dependence on MAO-B inhibition remains unclear. Here, indane-to-azaindane rasagiline isosteres (rac-2a and rac-2b) were developed to investigate whether neuroprotection can be decoupled from MAO-B inhibition. Direct regioselective oxidation of 4-azaindane catalyzed by Mn(OAc)₂/^tBuOOH afforded the key 4-azaindan-1-one intermediate (6a). In paraquat-insulted dopaminergic differentiated SH-SY5Y cells, both analogs showed neuroprotection at 10 and 100 μM, with rac-2b outperforming rasagiline. The azaindane analogs displayed markedly reduced MAO-B inhibition and no time-dependent inhibition. These findings demonstrate that rasagiline neuroprotection can be dissociated from MAO-B inhibition, supporting azaindane bioisosterism for exploring MAO-independent neuroprotection.

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通过茚一氮丹生物等构替代雷沙吉兰，将神经保护从MAO抑制中解耦

雷沙吉兰是一种具有神经保护作用的单胺氧化酶B （MAO-B）抑制剂，其对MAO-B抑制的依赖性尚不清楚。在这里，我们开发了茚-氮丹雷沙吉兰异构体（rac-2a和rac-2b）来研究神经保护是否可以从mao抑制中分离出来。Mn(OAc)2/ buooh催化4-叠氮丹直接区域选择性氧化得到关键的4-叠氮丹-1- 1中间体（6a）。在百草枯诱导多巴胺能分化的SH-SY5Y细胞中，两种类似物在10 μM和100 μM下均表现出神经保护作用，其中rac2b的效果优于格拉吉兰。氮杂丹类似物表现出明显降低mao抑制作用，无时间依赖性抑制作用。这些发现表明，雷沙吉兰的神经保护作用可以与MAO-B抑制分离，支持氮杂丹生物等构论探索mao非依赖性神经保护作用。

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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.