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

• Published in: Bioorganic chemistry 2024-12, Vol.153, p.107877, Article 107877
• Main Authors: Knez, Damijan, Wang, Fen, Duan, Wen-Xiang, Hrast Rambaher, Martina, Gobec, Stanislav, Cheng, Xiao-Yu, Wang, Xiao-Bo, Mao, Cheng-Jie, Liu, Chun-Feng, Frlan, Rok
• Format: Article
• Language: English
• Subjects: Animals; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; Azastilbene; Dose-Response Relationship, Drug; Humans; Inhibitors; Library; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase - metabolism; Monoamine oxidase B; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacology; Neurodegenerative diseases; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson’s disease; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107877

[Display omitted] •Azastilbene-based compounds synthesized as potent hMAO-B inhibitors.•Lead compounds showed nanomolar hMAO-B inhibition.•Selected compounds were selective for hMAO-B and inhibited cholinesterases.•Molecular docking identified key binding interactions with hMAO-B.•A lead compound reduced oxidative stress in a Parkinson’s disease cell model and improved motor function in a mouse model. 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.