2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2022 Aug 5;238:114503. doi: 10.1016/j.ejmech.2022.114503.
Jie Liu 1,  Lu Liu 1,  Lei Zheng 1,  Kai-Wen Feng 1,  Hai-Tao Wang 1,  Jiang-Ping Xu 2,  Zhong-Zhen Zhou 3
Affiliations

Affiliations

  • 1 Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 3 Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Pharmacy Department, Zhujiang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
PMID: 35689855 DOI: 10.1016/j.ejmech.2022.114503
Abstract

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.

Keywords

2,3-Dihydro-1H-inden-1-ones; AChE inhibitors; Alzheimer's disease; PDE4 inhibitors; Selectivity.

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