Rim Malek, Kinga Sałat, Perle Totoson, Tadeusz Karcz, Bernard Refouvelet, Anna Skrzypczak-Wiercioch, Maciej Maj, Alexey Simakov, Helene Martin, Agata Siwek, Natalia Szałaj, Justyna Godyń, Dawid Panek, Anna Więckowska, Krzysztof Jozwiak, Celine Demougeot, Katarzyna Kieć-Kononowicz, Fakher Chabchoub, Isabel Iriepa, José Marco-Contelles, Lhassane Ismaili
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引用次数: 0
Abstract
At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.
目前，应对阿尔茨海默病（AD）带来的复杂挑战最有希望的策略之一是开发新型多靶点配体（MTDLs）。为此，我们采用简单、经济的一锅式 Biginelli 三组分反应设计并合成了九种新型 MTDL。在这些新开发的化合物中，一种名为 3e 的特殊小分子成为了一种前景广阔的 MTDL。这种化合物能有效靶向与注意力缺失症相关的关键生物因素，包括同时抑制胆碱酯酶（ChEs）、选择性拮抗 H3 受体和阻断电压门控钙通道。此外，化合物 3e 对 H2O2 和 Aβ1-40 具有显著的神经保护活性，并能有效恢复用东莨菪碱治疗的 AD 小鼠在新物体识别任务中的认知功能，这证实该化合物可为有效治疗 AD 提供一种新颖的治疗方法。
期刊介绍：
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research
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