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1.
Arch Pharm (Weinheim) ; 345(7): 509-16, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22467516

RESUMEN

A new series of 2-(diethylaminoalkyl)-isoindoline-1,3-dione derivatives intended as dual binding site cholinesterase inhibitors were designed using molecular modeling and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and the formation of the ß-amyloid (Aß) plaques. For AChE inhibitory activity, the spectrophotometric method of Ellman and the electrophoretically mediated microanalysis assay were used, giving good results. Most of the synthesized compounds had AChE inhibitory activity with IC(50) values ranging from IC(50) = 0.9 to 19.5 µM and weak Aß anti-aggregation inhibitory activity. These results support the outcome of docking studies which tested compounds targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The most promising selective AChE inhibitors are compounds 10 (IC(50) = 1.2 µM) and 11 (IC(50) = 1.1 µM), with 6-7 methylene chains, which also inhibit Aß fibril formation.


Asunto(s)
Inhibidores de la Colinesterasa/síntesis química , Diseño de Fármacos , Isoindoles/síntesis química , Acetilcolinesterasa , Animales , Sitios de Unión , Butirilcolinesterasa , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Electrophorus , Caballos , Isoindoles/química , Isoindoles/farmacología , Modelos Moleculares , Estructura Molecular , Análisis de Regresión , Relación Estructura-Actividad , Especificidad por Sustrato
2.
Bioorg Med Chem ; 18(5): 2049-59, 2010 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-20149667

RESUMEN

Approved drugs for the treatment of Alzheimer's disease belong to the group of inhibitors of the acetylcholinesterase (AChE) and NMDA receptor inhibitors. However none of the drugs is able to combat or reverse the progression of the disease. Thus, the recently reported promising multitarget-directed molecule approach was applied here. Using the lead compound DUO3, which was found to be a potent inhibitor of the AChE and butyrylcholinesterase (BuChE) as well as an inhibitor of the formation of the amyloid (Abeta) plaque, new non-permanently positively charged derivatives were synthesized and biologically characterized. In contrast to DUO3 the new bisphenyl-substituted pyridinylidene hydrazones 5 are appropriate to cross the blood-brain barrier due to their pK(a) values and lipophilicity, and to inhibit both the AChE and BuChE. More important some of the pyridinylidene hydrazones inhibit the Abeta fibril formation completely and destruct the already formed fibrils significantly.


Asunto(s)
Acetilcolinesterasa/química , Péptidos beta-Amiloides/metabolismo , Butirilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Dihidropiridinas/química , Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides/química , Sitios de Unión , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Simulación por Computador , Dihidropiridinas/síntesis química , Dihidropiridinas/farmacología , Cinética , Modelos Moleculares , Relación Estructura-Actividad
3.
Eur J Pharm Sci ; 49(4): 603-13, 2013 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-23643737

RESUMEN

Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid ß fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC50=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.


Asunto(s)
Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Hidrazonas/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Células Endoteliales , Células HEK293 , Humanos , Peroxidación de Lípido/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo
4.
Eur J Pharm Sci ; 45(1-2): 169-83, 2012 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-22108346

RESUMEN

In this contribution, a chemical collection of aromatic compounds was screened for inhibition on butyrylcholinesterase (BChE)'s hydrolase activity using Ellman's reaction. A set of diarylimidazoles was identified as highly selective inhibitors of BChE hydrolase activity and amyloid ß (Aß) fibril formation. New derivatives were synthesized resulting in several additional hits, from which the most active was 6c, 4-(3-ethylthiophenyl)-2-(3-thienyl)-1H-imidazole, an uncompetitive inhibitor of BChE hydrolase activity (IC50 BChE=0.10 µM; K(i)=0.073 ± 0.011 µM) acting also on Aß fibril formation (IC50=5.8 µM). With the aid of structure-activity relationship (SAR) studies, chemical motifs influencing the BChE inhibitory activity of these imidazoles were proposed. These bifunctional inhibitors represent good tools in basic studies of BChE and/or promising lead molecules for AD therapy.


Asunto(s)
Amiloide/antagonistas & inhibidores , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Imidazoles/química , Imidazoles/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Butirilcolinesterasa/genética , Butirilcolinesterasa/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/efectos adversos , Evaluación Preclínica de Medicamentos , Electrophorus , Caballos , Humanos , Imidazoles/efectos adversos , Cinética , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Terapia Molecular Dirigida , Proteínas Recombinantes , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Tiofenos/efectos adversos , Tiofenos/química , Tiofenos/farmacología
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