| 5 | 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases显示文摘We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)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 h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/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. | Damijan Knez Daniel Diez-Iriepa Mourad Chioua Andrea Gottinger Milica Denic Fabien Chantegreil Florian Nachon Xavier Brazzolotto Anna Skrzypczak-Wiercioch Ane Meden Anja Pilar Janko Kos Simon akelj Jure Stojan Kinga Saat Julia Serrano Ana Patricia Fernández Aitana Sánchez-García Ricardo Martínez-Murillo Claudia Binda Francisco López-Muoz Stanislav Gobec JoséMarco-Contelles | 2023 | Acta Pharmaceutica Sinica B2023，13，5： | 0 |
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