20.500.12556/RUL-163955 Development of novel aza-stilbenes as a new class of selective MAO-B inhibitors for the treatment of Parkinson’s disease 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. neurodegenerative diseases Parkinson’s disease monoamine oxidase B inhibitors azastilbene library zaviralci monoaminooksidaze B azastilben nevrodegenerativne bolezni Parkinsonova bolezen true false true Angleški jezik Slovenski jezik Članek v reviji 2024-10-14 15:50:40 2024-10-14 15:50:49 2024-10-16 03:31:44 0000-00-00 00:00:00 2024 0 0 22 str. art. 107877 Vol. 153 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.831-003.8 0045-2068 10.1016/j.bioorg.2024.107877 211330051 1-s2.0-S004520682400782X-main.pdf 1-s2.0-S004520682400782X-main.pdf 1 DA140DE317F375768B746B1E84A96AA5 ca02aeac250884629d473287320b9e6ed90595376144e5628c0d15010f3c1fc4 898dd624-8a33-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=193970 https://www.sciencedirect.com/science/article/pii/S004520682400782X 1 18c0eea6-8a33-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=193969 Fakulteta za farmacijo 0 0 0