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

作　　者：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 

机构地区：[1]University of Ljubljana,Faculty of Pharmacy,Ljubljana 1000,Slovenia [2]Laboratory of Medicinal Chemistry(Institute of Organic Chemistry,CSIC),Madrid 28006,Spain [3]Departamento de Química Orgánicay Química Inorgánica,Alcaláde Henares,Madrid 28871,Spain [4]Department of Biology and Biotechnology,University of Pavia,Pavia 27100,Italy [5]Département de Toxicologie et Risques Chimiques,Institut de Recherche Biomédicale des Armées,Paris 91220,France [6]Department of Animal Anatomy and Preclinical Sciences,University Centre of Veterinary Medicine JU-UA,University of Agriculture in Krakow,Krakow 30-059,Poland [7]Institute of Biochemistry,Faculty of Medicine,University of Ljubljana,Ljubljana 1000,Slovenia [8]Department of Pharmacodynamics,Chair of Pharmacodynamics,Faculty of Pharmacy,Jagiellonian University Medical College,Krakow 30-688,Poland [9]Department of Translational Neurobiology,Neurovascular Research Group,Cajal Institute(CSIC),Madrid 28002,Spain [10]Biotechnology and Vegetal Biology Department,Escuela Técnica Superior de Ingeniería Agronómica,Alimentaria y de Biosistemas,Universidad Politécnica de Madrid,Madrid 28040,Spain [11]Faculty of Health,Camilo JoséCela University of Madrid(UCJC),Neuropsychopharmacology Unit,“Hospital 12 de Octubre”Research Institute,Madrid 28692,Spain

出　　处：《Acta Pharmaceutica Sinica B》2023年第5期2152-2175,共24页药学学报（英文版）

基　　金：MINECO(Government of Spain,grant number SAF-2015-65586-R);UCJC(grants"OPTICOMC903"and"NACONT")to JMC;ARRS(Slovenian Research Agency)core research funding P1-0208,P4-0127 and P1-0189,and project Z1-1859;Italian Ministry of Education,University and Research(MIUR,"Dipartimenti di Eccellenza Program 2018-2022-Dept.of Biology and Biotechnology L.Spallanzani",University of Pavia,Italy);the French Ministry of Armed Forces(Direction Générale des Armées and Service de Santédes Armées,France)under grant number NBC-5-C-4210。

摘　　要：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.

关 键 词：Quinolylnitrone BUTYRYLCHOLINESTERASE Monoamine oxidase B Alzheimer's disease Multifunctional ligands 6-Hydroxydopamine model Passive avoidance task Novel object recognition 

分 类 号：R741.05[医药卫生—神经病学与精神病学]