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

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

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.

• Jezik: Angleški jezik
• Ključne besede: chiral switch, resolution of enantiomers, Alzheimer's disease, butyrylcholinesterase, enzyme inhibitors
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2025
• Št. strani: 15 str.
• Številčenje: Vol. 420, art. 111670
• PID: 20.500.12556/RUL-175877
• UDK: 616.894
• ISSN pri članku: 0009-2797
• DOI: 10.1016/j.cbi.2025.111670
• COBISS.SI-ID: 250780931
• 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: kiralno stikalo, ločljivost enantiomerov, butirilholinesteraza, encimski zaviralci, Alzheimerjeva bolezen