N-propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors

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

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.

• Language: English
• Keywords: butyrylcholinesterase, acetylcholinesterase, monoamine oxidase, monoamine oxidase A, monoamine oxidase B, enzyme inhibitors, pyrrolidines
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: 15 str.
• Numbering: Vol. 420, art. 111681
• PID: 20.500.12556/RUL-175879
• UDC: 616.894:616-085
• ISSN on article: 0009-2797
• DOI: 10.1016/j.cbi.2025.111681
• COBISS.SI-ID: 250785283
• Publication date in RUL: 12.11.2025

Record is a part of a journal

• Title: Chemico-biological interactions
• Shortened title: Chem.-biol. interact.
• Publisher: Elsevier
• ISSN: 0009-2797
• COBISS.SI-ID: 1720335

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: butirilholinesteraza, acetilholinesteraza, monoaminooksidaza, monoaminooksidaza A, monoaminooksidaza B, zaviralci encimov, pirolidini, Alzheimerjeva bolezen, zdravljenje