1.8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases.
Damijan KNEZ ; Daniel DIEZ-IRIEPA ; Mourad CHIOUA ; Andrea GOTTINGER ; Milica DENIC ; Fabien CHANTEGREIL ; Florian NACHON ; Xavier BRAZZOLOTTO ; Anna SKRZYPCZAK-WIERCIOCH ; Anže MEDEN ; Anja PIŠLAR ; Janko KOS ; Simon ŽAKELJ ; Jure STOJAN ; Kinga SAŁAT ; Julia SERRANO ; Ana Patricia FERNÁNDEZ ; Aitana SÁNCHEZ-GARCÍA ; Ricardo MARTÍNEZ-MURILLO ; Claudia BINDA ; Francisco LÓPEZ-MUÑOZ ; Stanislav GOBEC ; José MARCO-CONTELLES
Acta Pharmaceutica Sinica B 2023;13(5):2152-2175
We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 μmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.
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