New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation

被引:39
作者
Bortolami, Martina [1 ]
Pandolfi, Fabiana [2 ]
De Vita, Daniela [3 ]
Carafa, Camilla [1 ]
Messore, Antonella [1 ]
Di Santo, Roberto [1 ,4 ]
Feroci, Marta [2 ]
Costi, Roberta [1 ,4 ]
Chiarotto, Isabella [2 ]
Bagetta, Donatella [5 ]
Alcaro, Stefano [5 ,6 ]
Colone, Marisa [7 ]
Stringaro, Annarita [7 ]
Scipione, Luigi [1 ]
机构
[1] Sapienza Univ Rome, Dept Chim & Tecnol Farmaco, Piazzale Aldo Moro 5, I-00185 Rome, Italy
[2] Sapienza Univ Rome, Dept Sci Base & Applicate Ingn, Via Castro Laurenziano 7, I-00161 Rome, Italy
[3] Sapienza Univ Rome, Dept Environm Biol, Ple A Moro 5, I-00185 Rome, Italy
[4] Sapienza Univ Rome, Fdn Cenci Bolognetti, Dept Chem & Technol Drug, Ist Pasteur, Piazzale Aldo Moro 5, I-00185 Rome, Italy
[5] Net4Sci Srl, Campus Univ S Venuta,Viale Europa, I-88100 Catanzaro, Italy
[6] Magna Graecia Univ Catanzaro, Dipartimento Sci Salute, Viale Europa, I-88100 Catanzaro, Italy
[7] Ist Super Sanita, Natl Ctr Drug Res & Evaluat, Viale Regina Elena, I-00161 Rome, Italy
关键词
Acetylcholinesterase inhibitors; Butyrylcholinesterase inhibitors; Metal chelators; Deferiprone derivatives; TARGET-DIRECTED LIGANDS; HUMAN ACETYLCHOLINESTERASE; ALZHEIMERS-DISEASE; BIOLOGICAL EVALUATION; CRYSTAL-STRUCTURE; PROTECTIVE ROLES; BUTYRYLCHOLINESTERASE; CHELATORS; DISCOVERY; THERAPY;
D O I
10.1016/j.ejmech.2020.112350
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In order to obtain multi-functional molecules for Alzheimer's disease, a series of deferiprone derivatives has been synthesized and evaluated in vitro with the hypothesis that they can restore the cholinergic tone and attenuate the dyshomeostasis of the metals mainly involved in the pathology. These compounds were designed as dual binding site AChE inhibitors: they possess an arylalkylamine moiety connected via an alkyl chain to a 3-hydroxy-4-pyridone fragment, to allow the simultaneous interaction with catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme. Deferiprone moiety and 2-aminopyridine, 2-aminopyrimidine or 2,4-diaminopyrimidine groups have been incorporated into these compounds, in order to obtain molecules potentially able to chelate bio-metals colocalized in Ab plaques and involved in the generation of radical species. Synthesized compounds were tested by enzymatic inhibition studies towards EeAChE and eqBChE using Ellman's method. The most potent EeAChE inhibitor is compound 5a, with a K-i of 788 +/- 51 nM, while the most potent eqBChE inhibitors are compounds 12 and 19, with Ki values of 182 +/- 18 nM and 258 +/- 25 nM respectively. Selected compounds, among the most potent cholinesterases inhibitors, were able to form complex with iron and in some cases with copper and zinc. Moreover, these compounds were characterized by low toxicity on U-87 MG Cell Line from human brain (glioblastoma astrocytoma). (C) 2020 Published by Elsevier Masson SAS.
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页数:17
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