20.500.12556/RUL-175877 Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease 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. chiral switch resolution of enantiomers Alzheimer's disease butyrylcholinesterase enzyme inhibitors kiralno stikalo ločljivost enantiomerov butirilholinesteraza encimski zaviralci Alzheimerjeva bolezen true false true Angleški jezik Slovenski jezik Članek v reviji 2025-11-12 10:28:37 2025-11-12 10:28:44 2026-06-17 15:38:58 0000-00-00 00:00:00 2025 0 0 15 str. art. 111670 Vol. 420 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.894 0009-2797 10.1016/j.cbi.2025.111670 250780931 1-s2.0-S000927972500300X-main.pdf 1-s2.0-S000927972500300X-main.pdf 1 391971EEC34DB34AF1CDF90BC9F11E79 48804c6c3607e02c5ca7d71256067cf0e50925b39dfd266053a38b79704062e7 102f36f3-bfaf-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=221804 https://www.sciencedirect.com/science/article/pii/S000927972500300X 1 a782fc8e-bfa9-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=221803 Fakulteta za farmacijo Medicinska fakulteta 0 0 0