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1.
Nanoscale ; 12(25): 13757-13770, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32573587

RESUMO

New lipid-based nanomaterials and multi-target directed ligands (MTDLs) based on sterically hindered phenol, containing a quaternary ammonium moiety (SHP-s-R, with s = 2,3) of varying hydrophobicity (R = CH2Ph and CnH2n+1, with n = 8, 10, 12, 16), have been prepared as potential drugs against Alzheimer's disease (AD). SHP-s-R are inhibitors of human cholinesterases with antioxidant properties. The inhibitory potency of SHP-s-R and selectivity ratio of cholinesterase inhibition were found to significantly depend on the length of the methylene spacer (s) and alkyl chain length. The compound SHP-2-16 showed the best IC50 for human AChE and the highest selectivity, being 30-fold more potent than for human BChE. Molecular modeling of SHP-2-16 binding to human AChE suggests that this compound is a dual binding site inhibitor that interacts with both the peripheral anionic site and catalytic active site. The relationship between self-assembly parameters (CMC, solubilization capacity, aggregation number), antioxidant activity and a toxicological parameter (hemolytic action on human red blood cells) was investigated. Two sterically hindered phenols (SHP-2-Bn and SHP-2-R) were loaded into L-α-phosphatidylcholine (PC) nanoparticles by varying the SHP alkyl chain length. For the brain AChE inhibition assay, PC/SHP-2-Bn/SHP-2-16 nanoparticles were administered to rats intranasally at a dose of 8 mg kg-1. The Morris water maze experiment showed that scopolamine-induced AD-like dementia in rats treated with PC/SHP-2-Bn/SHP-2-16 nanoparticles was significantly reduced. This is the first example of cationic SHP-phospholipid nanoparticles for inhibition of brain cholinesterases realized by the use of intranasal administration. This route has promising potential for the treatment of AD.


Assuntos
Doença de Alzheimer , Administração Intranasal , Doença de Alzheimer/tratamento farmacológico , Animais , Inibidores da Colinesterase/farmacologia , Lipídeos/uso terapêutico , Fenol/uso terapêutico , Fenóis , Ratos , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 185: 111787, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675511

RESUMO

New uncharged conjugates of 6-methyluracil derivatives with imidazole-2-aldoxime and 1,2,4-triazole-3-hydroxamic acid units were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. Using paraoxon (POX) as a model organophosphate, it was shown that 6-methyluracil derivatives linked with hydroxamic acid are able to reactivate POX-inhibited human acetylcholinesterase (AChE) in vitro. The reactivating efficacy of one compound (5b) is lower than that of pyridinium-2-aldoxime (2-PAM). Meanwhile, unlike 2-PAM, in vivo study showed that the lead compound 5b is able: (1) to reactivate POX-inhibited AChE in the brain; (2) to decrease death of neurons and, (3) to prevent memory impairment in rat model of POX-induced neurodegeneration.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Ácidos Hidroxâmicos/farmacologia , Paraoxon/antagonistas & inibidores , Uracila/análogos & derivados , Animais , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Humanos , Ácidos Hidroxâmicos/química , Ligantes , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Paraoxon/farmacologia , Paraoxon/toxicidade , Teoria Quântica , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Uracila/síntese química , Uracila/química , Uracila/farmacologia
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