Targeting Alzheimer's pathology: Tetralone- and thiochromanone-based benzyl pyridinium derivatives as promising multi-target-directed ligands

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-08-23 DOI:10.1016/j.bmc.2025.118369

Anjali Sobha , Lekshmy Krishnan , Shareef Shaik , Aravinda Pai , Jayamurthy Purushothaman , Kumaran Alaganandam , Sasidhar B. Somappa

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Abstract

The lack of therapeutics that can fully halt the progression of Alzheimer's disease (AD) has prompted us to design and synthesize a series of tetralone/thiochromanone-based benzyl pyridinium salts (4a-4s) aimed at modulating multiple pathological targets associated with AD. Preliminary screening for cholinesterase and monoamine oxidase inhibition identified compounds 4e and 4g as the most potent inhibitors (AChE IC₅₀: 2.17 ± 0.13 μM and 2.29 ± 0.15 μM; MAO-B IC₅₀: 0.89 ± 0.07 μM and 0.92 ± 0.16 μM, respectively). Both compounds also demonstrated anti-neuroinflammatory activity by reducing pro-inflammatory cytokines (TNF-α and IL-6) and downregulating COX-2 and NF-κB signalling pathways. Additionally, 4e exhibited significant ROS scavenging ability by mitigating oxidative stress and conferred neuroprotection in SH-SY5Y cells by attenuating Aβ₁₋₄₂-induced mitochondrial dysfunction and apoptosis. Collectively, these findings position compound 4e as a promising multi-target-directed ligand (MTDL) for the treatment of AD.

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靶向阿尔茨海默病病理：四酮和硫代变色酮基苄基吡啶衍生物作为有前途的多靶点定向配体

由于缺乏能够完全阻止阿尔茨海默病（AD）进展的治疗方法，我们设计并合成了一系列基于四酮/硫代铬酮的苄基吡啶盐（4a-4s），旨在调节与AD相关的多种病理靶点。对胆碱酯酶和单胺氧化酶抑制的初步筛选发现，化合物4e和4g是最有效的抑制剂（AChE IC₅₀：2.17±0.13 μM和2.29±0.15 μM; maob IC₅₀：0.89±0.07 μM和0.92±0.16 μM）。这两种化合物还通过降低促炎细胞因子（TNF-α和IL-6）和下调COX-2和NF-κB信号通路显示出抗神经炎症活性。此外，4e通过减轻氧化应激表现出显著的ROS清除能力，并通过减弱Aβ₁−₄2诱导的线粒体功能障碍和凋亡，赋予SH-SY5Y细胞神经保护作用。总的来说，这些发现将化合物4e定位为治疗AD的有前途的多靶点定向配体（MTDL）。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.