Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease

Košak, Urban (author), Knez, Damijan (author), Ferjančič Benetik, Svit (author), Mastnak-Sokolov, Peter (author), Pišlar, Anja (author), Horvat, Selena (author), Stojan, Jure (author), Gobec, Stanislav (author)

Butyrylcholinesterase (BChE) is a viable drug target to alleviate the symptoms of Alzheimer's disease (AD). We recently developed and biologically evaluated racemic N-benzylpiperidine-based naphthalene-2-sulfonamide 2, a nanomolar BChE inhibitor with procognitive effects. To optimize it, we performed a chiral switch. Using semi-preparative chiral HPLC, we isolated the pure enantiomers (R)-(−)-2 and (S)-(+)-2 and confirmed that (R)-(−)-2 is the eutomer and (S)-(+)-2 is the distomer with respect to human (h)BChE inhibition. Notably, (R)-(−)-2 is a less potent inhibitor of human acetylcholinesterase (hAChE) than both racemate 2 and (S)-(+)-2, which is advantageous, since AChE inhibition is associated with undesirable peripheral parasympathomimetic adverse effects. The crystal structures of hBChE in complexes with each enantiomer revealed distinct binding poses. The crystal structure of hBChE in complex with (R)-(−)-2 confirmed our previous hypothesis that only the (R)-(−)-2 is bound in the active site of hBChE when the racemate is crystallized. The synthesis of (R)-2 hydrochloride has a higher overall yield (73 %) than the synthesis of racemate 2 hydrochloride (64 %) and is safer as it avoids the use of LiAlH$_4$. (R)-(−)-2 has in vivo efficacy in mice with scopolamine-induced AD-like symptoms, and (R)-(−)-2 is less toxic in mice LD$_{50}$ = 169 mg/kg) than racemate 2 LD$_{50}$ = 112 mg/kg). These results support the chiral switch from racemate 2 to (R)-(−)-2 as a safer and more selective lead compound in the anti-AD drug development pipeline.

• Language: English
• Keywords: chiral switch, resolution of enantiomers, Alzheimer's disease, butyrylcholinesterase, enzyme inhibitors
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: 15 str.
• Numbering: Vol. 420, art. 111670
• PID: 20.500.12556/RUL-175877
• UDC: 616.894
• ISSN on article: 0009-2797
• DOI: 10.1016/j.cbi.2025.111670
• COBISS.SI-ID: 250780931
• 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: kiralno stikalo, ločljivost enantiomerov, butirilholinesteraza, encimski zaviralci, Alzheimerjeva bolezen