N-propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors

Košak, Urban (avtor), Knez, Damijan (avtor), Pišlar, Anja (avtor), Horvat, Selena (avtor), Žakelj, Simon (avtor), Igert, Alexandre (avtor), Dias, Jose (avtor), Nachon, Florian (avtor), Brazzolotto, Xavier (avtor), Gobec, Stanislav (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: butyrylcholinesterase, acetylcholinesterase, monoamine oxidase, monoamine oxidase A, monoamine oxidase B, enzyme inhibitors, pyrrolidines
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2025
• Št. strani: 15 str.
• Številčenje: Vol. 420, art. 111681
• PID: 20.500.12556/RUL-175879
• UDK: 616.894:616-085
• ISSN pri članku: 0009-2797
• DOI: 10.1016/j.cbi.2025.111681
• COBISS.SI-ID: 250785283
• Datum objave v RUL: 12.11.2025

Gradivo je del revije

• Naslov: Chemico-biological interactions
• Skrajšan naslov: Chem.-biol. interact.
• Založnik: Elsevier
• ISSN: 0009-2797
• COBISS.SI-ID: 1720335

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: butirilholinesteraza, acetilholinesteraza, monoaminooksidaza, monoaminooksidaza A, monoaminooksidaza B, zaviralci encimov, pirolidini, Alzheimerjeva bolezen, zdravljenje