Development of novel aza-stilbenes as a new class of selective MAO-B inhibitors for the treatment of Parkinson's disease

  • Bioorg Chem. 2024 Dec:153:107877. doi: 10.1016/j.bioorg.2024.107877.
Damijan Knez  1 ,  Fen Wang  2 ,  Wen-Xiang Duan  3 ,  Martina Hrast Rambaher  1 ,  Stanislav Gobec  1 ,  Xiao-Yu Cheng  3 ,  Xiao-Bo Wang  4 ,  Cheng-Jie Mao  3 ,  Chun-Feng Liu  5 ,  Rok Frlan  6
Affiliations
  • 1. University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva 7, 1000 Ljubljana, Slovenia.
  • 2. Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China.
  • 3. Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
  • 4. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China.
  • 5. Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China. Electronic address: [email protected].
  • 6. University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: [email protected].
PMID: 39396452 DOI: 10.1016/j.bioorg.2024.107877
Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of nigrostriatal dopaminergic neurons. Inhibitors of Monoamine Oxidase B (MAO-B) have shown promise in alleviating motor symptoms and reducing oxidative stress associated with PD. In this study, we report the novel use of an azastilbene-based compound library for screening human (h)MAO-B, followed by optimization of initial hits to obtain compounds with low nanomolar inhibitory potencies (compound 9, IC50 = 42 nM) against hMAO-B. To ensure specificity and minimize false positives due to non-specific hydrophobic interactions, we performed comprehensive selectivity profiling against hMAO-A, butyrylcholinesterase (hBChE) and acetylcholinesterase (hAChE) - Enzymes with hydrophobic active sites that are structurally distinct from hMAO-B. Docking analysis with Glide provided valuable insights into the binding interactions between the inhibitors and hMAO-B and also explained the selectivity against hMAO-A. In the cell-based model of Parkinson's disease, one of the compounds significantly reduced rotenone-induced accumulation of Reactive Oxygen Species. In addition, these compounds showed a protective effect against acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunction in PD model mice and reduced MPTP-induced loss of striatal tyrosine hydroxylase-positive neurons in the substantia nigra. These results make azastilbene-based compounds a promising new class of hMAO-B inhibitors with potential therapeutic applications in Parkinson's disease and related neurodegenerative disorders.

Keywords
Azastilbene; Inhibitors; Library; Monoamine oxidase B; Neurodegenerative diseases; Parkinson’s disease.
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