8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseasesKnez, Damijan (Avtor) Meden, Anže (Avtor) Pišlar, Anja (Avtor) Kos, Janko (Avtor) Žakelj, Simon (Avtor) Stojan, Jure (Avtor) Gobec, Stanislav (Avtor) Marco-Contelles, José (Avtor) quinolylnitronebutyrylcholinesterasemonoamine oxidase BAlzheimer's diseasemultifunctional ligands6-hydroxydopamine modelpassive avoidance tasknovel object recognitionWe 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 (IC$_{50}$ = 1.06 ± 0.31 nmol/L) and hMAO-B (IC$_{50}$ = 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 19.20232023-06-09 08:39:21Članek v reviji146733sl