8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases
作者机构：University of LjubljanaFaculty of PharmacyLjubljana 1000Slovenia Laboratory of Medicinal Chemistry(Institute of Organic ChemistryCSIC)Madrid 28006Spain Departamento de Química Orgánicay Química InorgánicaAlcaláde HenaresMadrid 28871Spain Department of Biology and BiotechnologyUniversity of PaviaPavia 27100Italy Département de Toxicologie et Risques ChimiquesInstitut de Recherche Biomédicale des ArméesParis 91220France Department of Animal Anatomy and Preclinical SciencesUniversity Centre of Veterinary Medicine JU-UAUniversity of Agriculture in KrakowKrakow 30-059Poland Institute of BiochemistryFaculty of MedicineUniversity of LjubljanaLjubljana 1000Slovenia Department of PharmacodynamicsChair of PharmacodynamicsFaculty of PharmacyJagiellonian University Medical CollegeKrakow 30-688Poland Department of Translational NeurobiologyNeurovascular Research GroupCajal Institute(CSIC)Madrid 28002Spain Biotechnology and Vegetal Biology DepartmentEscuela Técnica Superior de Ingeniería AgronómicaAlimentaria y de BiosistemasUniversidad Politécnica de MadridMadrid 28040Spain Faculty of HealthCamilo JoséCela University of Madrid(UCJC)Neuropsychopharmacology Unit“Hospital 12 de Octubre”Research InstituteMadrid 28692Spain
出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)
年 卷 期：2023年第13卷第5期
页 面：2152-2175页
核心收录：
学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100204[医学-神经病学] 10[医学]
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。
主 题：Quinolylnitrone Butyrylcholinesterase Monoamine oxidase B Alzheimer's disease Multifunctional ligands 6-Hydroxydopamine model Passive avoidance task Novel object recognition
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.
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