Université de Franche-Comté, INSERM, UMR 1322 LINC, F-25000 Besançon, France.
Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, B. P 802, Sfax 3000, Tunisia.
ACS Chem Neurosci. 2024 Sep 18;15(18):3363-3383. doi: 10.1021/acschemneuro.4c00341. Epub 2024 Aug 29.
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 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 H receptors, and blocking voltage-gated calcium channels. Additionally, compound exhibited remarkable neuroprotective activity against HO and Aβ, 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）所带来的复杂挑战最有前景的策略之一是开发新型多靶标导向配体（MTDL）。为此，我们设计并使用简单高效的一锅法Biginelli 三组分反应合成了 9 种新型 MTDL。在这些新开发的化合物中，有一种特别的小分子，命名为 ，它是一种很有前途的 MTDL。这种化合物可以有效针对与 AD 相关的关键生物因素，包括同时抑制胆碱酯酶（ChE）、选择性拮抗 H 受体和阻断电压门控钙通道。此外，化合物 对 HO 和 Aβ 表现出显著的神经保护活性，并能有效恢复 AD 小鼠在新物体识别任务中因东莨菪碱治疗而受损的认知功能，证实该化合物可能为有效治疗 AD 提供一种新颖而有创新性的治疗方法。
