20.500.12556/RUL-146733 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases 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 (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. quinolylnitrone butyrylcholinesterase monoamine oxidase B Alzheimer's disease multifunctional ligands 6-hydroxydopamine model passive avoidance task novel object recognition kinolilnitron butirilholinesteraza monoaminooksidaza B multifunkcionalni ligandi alzheimerjeva bolezen model 6-hidroksidopamina naloga pasivnega izogibanja prepoznavanje novih predmetov encimska kinetika nevrodegenerativne bolezni true false true Angleški jezik Slovenski jezik Članek v reviji 2023-06-09 08:39:21 2023-06-09 08:39:25 2023-06-13 14:20:42 0000-00-00 00:00:00 2023 0 0 Str. 2152-2175 iss. 5 Vol. 13 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.831-003.8 2211-3843 10.1016/j.apsb.2023.01.013 139883267 1-s2.0-S2211383523000138-main.pdf 1-s2.0-S2211383523000138-main.pdf 1 9793F63F5D79BF0318A2A53CD1F6D6EB 39a611545a46b7e740b8702ef3d9d3c729bf1a0c6d00afff9a98a32253462076 7d77521c-0693-11ee-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=170014 https://www.sciencedirect.com/science/article/pii/S2211383523000138 1 0d4b3e19-0690-11ee-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=170011 Fakulteta za farmacijo Medicinska fakulteta 0 0 0