20.500.12556/RUL-175879 N-propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors Butyrylcholinesterase (BChE) inhibitors are or could be used for the treatment of Alzheimer's disease, canine cognitive dysfunction, depression, multiple sclerosis, heroin abuse and metabolic disorders. Monoamine oxidase (MAO) inhibitors are or could be used for the treatment of depression, anxiety, Alzheimer's disease, Parkinson's disease, cancer, cardiovascular disease and chronic inflammatory diseases. We have designed, synthesized, and evaluated ten new N-propargylpyrrolidine-based inhibitors of these enzymes. Sulfonamide 10 is the most potent human (h)BChE IC$_{50}$ = 0.203 μM) of the series, and secondary carboxamide 1 is a time-dependent and irreversible inhibitor of hMAO-A IC$_{50}$ = 6.42 μM) and hMAO-B IC$_{50}$ = 7.83 μM). The X-ray crystal structures of carboxamide 4 [IC$_{50}$(hBChE) = 3.89 μM] and sulfonamide 10 with hBChE confirmed our previous observation that carboxamides and sulfonamides have distinct binding poses in the active site of hBChE. The X-ray crystal structure of the complex of pyrrolidine 4 with hBChE also revealed a distinct binding pose compared to its direct piperidine analogue (PDB code 5LKR). Furthermore, compounds 1 and 10 should be able to cross the blood-brain barrier, exhibit low cytotoxicity (>50 μM) in two cell lines and protect against amyloid β$_{1-42}$-induced neuronal cell death. butyrylcholinesterase acetylcholinesterase monoamine oxidase monoamine oxidase A monoamine oxidase B enzyme inhibitors pyrrolidines butirilholinesteraza acetilholinesteraza monoaminooksidaza monoaminooksidaza A monoaminooksidaza B zaviralci encimov pirolidini Alzheimerjeva bolezen zdravljenje true false true Angleški jezik Slovenski jezik Članek v reviji 2025-11-12 11:22:28 2025-11-12 11:22:32 2026-06-17 15:58:43 0000-00-00 00:00:00 2025 0 0 15 str. art. 111681 Vol. 420 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.894:616-085 0009-2797 10.1016/j.cbi.2025.111681 250785283 1-s2.0-S0009279725003114-main.pdf 1-s2.0-S0009279725003114-main.pdf 1 8410E1B375DE8AB7D6F3C52958E8AC5C fef99e0ad906fd1b5dd4e15d5c778be517bb6ed74bfaf31f9e1dfb5e9cbd7819 10314e32-bfb2-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=221807 https://www.sciencedirect.com/science/article/pii/S0009279725003114 1 2c35b459-bfb1-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=221806 Fakulteta za farmacijo 0 0 0