Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4/AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimer's disease

摘要

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 mu M) and PDE4D (IC50 = 1.88 mu M). 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 antineuroinflammation than the donepezil and drug combination (donepezil + rolipram) groups. These results suggest that 12C is a promising multifunctional agent for the treatment of AD.

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