Development of novel aza-stilbenes as a new class of selective MAO-B inhibitors for the treatment of Parkinson’s diseaseKnez, Damijan (Avtor) Wang, Fen (Avtor) Duan, Wen-Xiang (Avtor) Hrast Rambaher, Martina (Avtor) Gobec, Stanislav (Avtor) Cheng, Xiao-Yu (Avtor) Wang, Xiao-Bo (Avtor) Mao, Cheng-Jie (Avtor) Liu, Chun-Feng (Avtor) Frlan, Rok (Avtor) neurodegenerative diseasesParkinson’s diseasemonoamine oxidase BinhibitorsazastilbenelibraryParkinson’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.20242024-10-14 15:50:40Članek v reviji163955UDK: 616.831-003.8ISSN pri članku: 0045-2068DOI: 10.1016/j.bioorg.2024.107877COBISS_ID: 211330051sl