Discovery of 4-benzylpiperazinequinoline BChE inhibitor that suppresses neuroinflammation for the treatment of Alzheimer's disease

  • Eur J Med Chem. 2024 Jun 5:272:116463. doi: 10.1016/j.ejmech.2024.116463.
Ying Chen  1 ,  Weiting Zhang  2 ,  Qi Li  2 ,  Huanfang Xie  2 ,  Shuaishuai Xing  2 ,  Xin Lu  2 ,  Weiping Lyu  2 ,  Baichen Xiong  2 ,  Yuanyuan Wang  2 ,  Wei Qu  3 ,  Wenyuan Liu  2 ,  Heng Chi  4 ,  Xiaolong Zhang  4 ,  Feng Feng  5 ,  Haopeng Sun  6
Affiliations
  • 1. Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 2. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 3. School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
  • 4. Jiangsu Drug Development Engineering Center for Central Degenerative Disease, Jiangsu Food and Pharmaceuticals Science College, 223005, China.
  • 5. School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
  • 6. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
PMID: 38704944 DOI: 10.1016/j.ejmech.2024.116463
Abstract

Butyrylcholinesterase (BChE) has attracted wide interest as a promising target in Alzheimer's disease (AD) investigation. BChE is considered to play a compensable role of hydrolyzing acetylcholine (ACh), and its positive correlation with β-amyloid (Aβ) deposition also promotes disease progression. Herein, we uncovered a selective potent BChE Inhibitor S21-1011 (eqBChE IC50 = 0.059 ± 0.006 μM, hBChE IC50 = 0.162 ± 0.069 μM), which presented satisfactory druggability and therapeutic efficacy in AD models. In pharmacokinetics (PK) studies, S21-1011 showed excellent blood-brain barrier (BBB) permeability, metabolism stability and high oral-bioavailability. In pharmacodynamic (PD) studies, it protected neural cells from toxicity and inflammation stimulation in vitro. Besides, it also exerted anti-inflammatory effect and alleviated cognitive impairment in mice models induced by lipopolysaccharides (LPS) and Aβ. Generally, this compound has been confirmed to function as a neuroprotector and cognition improver in various AD pathology-like models. Therefore, S21-1011, a novel potent BChE Inhibitor, could be considered as a potential anti-AD candidate worthy of more profound investigation.

Keywords
Alzheimer's disease (AD); Butyrylcholinesterase (BChE); Neuroprotector; Oxidative stress; Small molecule inhibitors; Targeted therapy.
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