Rational design,synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity |
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| Affiliation: | 1. Collaborative Innovation Centre of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, PR China;2. College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, PR China;3. School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, PR China;1. Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS) Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;2. Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;3. Departamento de Química Orgánica e Instituto de Investigación Sanitaria Galicia Sur (IISGS), Universidade de Vigo, 36310 Vigo, Spain;4. Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, 35131 Padova, Italy;5. Departamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;1. Department of Chimica e Tecnologia del Farmaco, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185, Rome, Italy;2. Department of Scienze di Base e Applicate per l’Ingegneria, Sapienza University of Rome, via Castro Laurenziano 7, I-00161, Rome, Italy;3. Department of Environmental Biology, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy;4. Istituto Pasteur, Fondazione Cenci Bolognetti, Department of Chemistry and Technology of Drug, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185, Rome, Italy;5. Net4Science s.r.l., Campus universitario “S. Venuta”, Viale Europa, 88100, Catanzaro, Italy;6. Dipartimento di Scienze della Salute, Università“Magna Græcia” di Catanzaro, Viale Europa, 88100, Catanzaro, Italy;7. National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 00161, Rome, Italy;1. College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 311402, PR China;2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, PR China;1. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, via E. Orabona 4, 70125, Bari, Italy;2. Istituto Tumori IRCCS Giovanni Paolo II, viale O. Flacco 65, 70124, Bari, Italy |
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| Abstract: | A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC50 value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-β1-42 (Aβ1-42) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression. |
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| Keywords: | Alzheimer’s disease 3-Hydroxypyridin-4-one Iron chelators MAO-B inhibitors Multitarget agents AD" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" Alzheimer's disease ACh" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" acetylcholine DCC" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" dicyclohexylcarbodiimide DCFH-DA" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" 2, 7-dichlorofluorescein DCM" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" dichloromethane DCU" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ," },{" #name" :" italic" ," _" :" N′" },{" #name" :" __text__" ," _" :" -dicyclohexylurea DFP" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" Deferiprone DMAP" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" 4-(dimethylamino)pyridine DMF" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" ," },{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" -dimethylformamide HPO" },{" #name" :" keyword" ," $" :{" id" :" k0135" }," $$" :[{" #name" :" text" ," _" :" 3-hydroxypyridin-4-one MAO" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" monoamine oxidase MAO-B" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" MAO isoenzyme B, monoamine oxidase B MTDLs" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," _" :" multitarget-directed ligands MTT" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," _" :" methyl thiazolyl tetrazolium ROS" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" reactive oxygen species SAR" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" structure-activity relationship |
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