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

Knez, Damijan (author), Wang, Fen (author), Duan, Wen-Xiang (author), Hrast, Martina (author), Gobec, Stanislav (author), Cheng, Xiao-Yu (author), Wang, Xiao-Bo (author), Mao, Cheng-Jie (author), Liu, Chun-Feng (author), Frlan, Rok (author)

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, IC$_{50}$ = 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.

• Language: English
• Keywords: neurodegenerative diseases, Parkinson’s disease, monoamine oxidase B, inhibitors, azastilbene, library
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 22 str.
• Numbering: Vol. 153, art. 107877
• PID: 20.500.12556/RUL-163955
• UDC: 616.831-003.8
• ISSN on article: 0045-2068
• DOI: 10.1016/j.bioorg.2024.107877
• COBISS.SI-ID: 211330051
• Publication date in RUL: 14.10.2024

Record is a part of a journal

• Title: Bioorganic chemistry
• Shortened title: Bioorg. chem.
• Publisher: Elsevier
• ISSN: 0045-2068
• COBISS.SI-ID: 25099008

Licences

• License: CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
• Link: http://creativecommons.org/licenses/by-nc/4.0/
• Description: A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.

Secondary language

• Language: Slovenian
• Keywords: zaviralci monoaminooksidaze B, azastilben, nevrodegenerativne bolezni, Parkinsonova bolezen