Recently, the discovery of multifunctional molecules that target different factors in the treatment of dementia is a significant research area. Both PDE4 and AChE inhibitors display improvement in cognitive and memory function. In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4/AChE inhibitors to treat Alzheimer's disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC₅₀ = 0.28 μM) and PDE4D (IC₅₀ = 1.88 μM). Compared with donepezil, 12C revealed a comparable neuroprotective effect. Moreover, 12C exhibited comparable AChE inhibitory activity with donepezil in the hippocampus of AD model mice. Interestingly, 12C displayed more potent anti-neuroinflammation than the donepezil and drug combination (donepezil + rolipram) groups. These results suggest that 12C is a promising multifunctional agent for the treatment of AD.

最近，针对不同因素治疗痴呆症的多功能分子的发现是一个重要的研究领域。PDE4 和 AChE 抑制剂都显示出认知和记忆功能的改善。在这项研究中，设计、合成和评估了 28 种新型 2,3-dihydro-1 H -inden-1-ones 作为基于儿茶酚醚的双重 PDE4/AChE 抑制剂来治疗阿尔茨海默病 (AD)。在这些化合物中，在茚满酮环的 6 位带有 2-(哌啶-1-基)乙氧基的12C对 AChE (IC ₅₀  = 0.28 μM) 和 PDE4D (IC ₅₀  = 1.88 μM)表现出令人满意的抑制活性和选择性。 . 与多奈哌齐相比，12C揭示了类似的神经保护作用。此外，12C在 AD 模型小鼠的海马中表现出与多奈哌齐相当的 AChE 抑制活性。有趣的是，12C显示出比多奈哌齐和药物组合（多奈哌齐 + 咯利普兰）组更有效的抗神经炎症。这些结果表明12C是一种很有前途的治疗 AD 的多功能药物。