Citation: Zhi-Pei Sang, Teng Xue, Qian-Ru Xing, Qi-Yao Zhang, Hong-Song Chen, Xue Wang, Fu-Rong Zhang, Wen-Ling Fu, Wu Dong, Shu-Heng Huang, Yi-You Huang, Hai-Bin Luo. Discovery of α-mangostin derivatives as novel PDE4 inhibitors for the treatment of Alzheimer's disease: An artificial intelligence-driven synergized strategy[J]. Chinese Chemical Letters, ;2026, 37(5): 111318. doi: 10.1016/j.cclet.2025.111318 shu

Discovery of α-mangostin derivatives as novel PDE4 inhibitors for the treatment of Alzheimer's disease: An artificial intelligence-driven synergized strategy

Zhi-Pei Sang ^{a, 1} ,
Teng Xue ^{a, 1} ,
Qian-Ru Xing ^{a, 1} ,
Qi-Yao Zhang ^a ,
Hong-Song Chen ^b ,
Xue Wang ^a ,
Fu-Rong Zhang ^a ,
Wen-Ling Fu ^a ,
Wu Dong ^b ,
Shu-Heng Huang ^{a, *,} ,
Yi-You Huang ^{a, *,} ,
Hai-Bin Luo ^{a, c, *,}

a.
Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
b.
College of Animal Science and Technology. Inner Mongolia Minzu University, Tongliao 028000, China
c.
Song Li's Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572000, China

shhuang@hainanu.edu.cn

hyyou@hainanu.edu.cn

hbluo@hainanu.edu.cn

Received Date: 6 February 2025
Revised Date: 13 May 2025
Accepted Date: 14 May 2025
Available Online: 16 May 2025

Figures(4)

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder with no effective therapeutic agents currently available. Inhibiting phosphodiesterase 4 (PDE4) has emerged as a promising strategy for AD treatment. In this study, we employed a synergistic approach combining generative recurrent neural network (RNN)-driven combinatorial compound design, virtual screening, and structure-activity relationship (SAR) analysis to discover novel PDE4 inhibitors. Utilizing α-mangostin as a hit compound (half maximal inhibitory concentration (IC₅₀) = 1.31 µmol/L), we identified a novel PDE4 inhibitor, 13d (IC₅₀ = 72.8 nmol/L) with moderate liver microsomal stability (rat liver microsomes (RLM), t_1/2 = 32.4 min). In vitro activity results indicated that 13d exhibited favorable anti-inflammatory effects and promising neuroprotective activity. In vivo experiments demonstrated that 13d significantly improved AlCl₃-induced zebrafish AD model by inhibiting PDE4 and reducing inflammatory cytokine. Further, 13d significantly alleviated AlCl₃/d-galactose-induced AD mouse model. These findings highlight the potent PDE4 inhibitor 13d with promising anti-AD activity, underscoring the potential of artificial intelligence-driven drug discovery for novel therapeutic agents for AD.
- Alzheimer's disease,
- Generative recurrent neural network,
- α-Mangostin,
- PDE4 inhibitor,
- In vivo study
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