Insights into Structure-Activity Relationships of 3-Arylhydrazonoindolin-2-One Derivatives for Their Multitarget Activity on ß-Amyloid Aggregation and Neurotoxicity.
Molecules
; 23(7)2018 06 26.
Article
en En
| MEDLINE
| ID: mdl-29949947
ABSTRACT
Despite the controversial outcomes of clinical trials executed so far, the prevention of ß-amyloid (Aß) deposition and neurotoxicity by small molecule inhibitors of Aß aggregation remains a target intensively pursued in the search of effective drugs for treating Alzheimer's disease (AD) and related neurodegeneration syndromes. As a continuation of previous studies, a series of new 3-(2-arylhydrazono)indolin-2-one derivatives was synthesized and assayed, investigating the effects of substitutions on both the indole core and arylhydrazone moiety. Compared with the reference compound 1, we disclosed equipotent derivatives bearing alkyl substituents at the indole nitrogen, and fairly tolerated bioisosteric replacements at the arylhydrazone moiety. For most of the investigated compounds, the inhibition of Aß40 aggregation (expressed as pIC50) was found to be correlated with lipophilicity, as assessed by a reversed-phase HPLC method, through a bilinear relationship. The N¹-cyclopropyl derivative 28 was tested in cell-based assays of Aß42 oligomer toxicity and oxidative stress induced by hydrogen peroxide, showing significant cytoprotective effects. This study confirmed the versatility of isatin in preparing multitarget small molecules affecting different biochemical pathways involved in AD.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
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Agregado de Proteínas
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Indoles
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Neurotoxinas
Límite:
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article