8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

• DOI: 10.1016/j.apsb.2023.01.013
• Publication Date: 2023-01-19T20:38:38Z
• Authors: Damijan Knez; Daniel Diez-Iriepa; Mourad Chioua; Andrea Gottinger; Milica Denic; Fabien Chantegreil; Florian Nachon; Xavier Brazzolotto; Anna Skrzypczak-W...; Anže Meden; Anja Pišlar; Janko Kos; Simon Žakelj; Jure Stojan; Kinga Sałat; Julia Serrano; Ana Patricia Fern...; Aitana Sánchez-Ga...; Ricardo Martínez-...; Claudia Binda; Francisco López-M...; Stanislav Gobec; José Marco-Contelles
• Keywords: 0301 basic medicine; Multifunctional ligand; prepoznavanje novih predmetov; 6-hydroxydopamine model; Novel object recognition; 610; Passive avoidance task; multifunkcionalni ligandi; RM1-950; multifunctional ligands; butirilholinesteraza; Quinolylnitrone; 03 medical and health sciences; info:eu-repo/classification/udc/616.831-003.8; novel object recognition; 6-Hydroxydopamine model; Monoamine oxidase B; passive avoidance task; quinolylnitrone; naloga pasivnega izogibanja; encimska kinetika; Multifunctional ligands; Alzheimer's disease; 540; alzheimerjeva bolezen; nevrodegenerativne bolezni; 3. Good health; kinolilnitron; Butyrylcholinesterase; butyrylcholinesterase; monoamine oxidase B; model 6-hidroksidopamina; monoaminooksidaza B; Original Article; Therapeutics. Pharmacology; Alzheimer’s disease

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) monoamine oxidases (hMAO-A/B) for therapy neurodegenerative diseases. 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 hBChE (IC50 = 1.06 ± 0.31 nmol/L) hMAO-B 4.46 0.18 μmol/L). The crystal structures with provided structural basis binding, which was further studied by enzyme kinetics. Compound acted free radical scavenger biometal chelator, crossed blood-brain barrier, not cytotoxic, neuroprotective properties in 6-hydroxydopamine cell model Parkinson's disease. In addition, vivo studies anti-amnesic effect scopolamine-induced mouse AD without adverse effects on motoric function coordination. Importantly, chronic treatment double transgenic APPswe-PS1δE9 mice reduced amyloid plaque load hippocampus cortex female mice, underscoring disease-modifying 19.