Journal
MOLECULES
Volume 23, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/molecules23071544
Keywords
beta-amyloid aggregation inhibitors; indolin-2-ones; Alzheimer's disease; quantitative structure-activity relationships; multitarget activity
Funding
- APQ Research Apulian Region FutureInResearch-Regional program for smart specialization and social and environmental sustainability Fondo di Sviluppo e Coesione 2007-2013 [FKY7YJ5]
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Despite the controversial outcomes of clinical trials executed so far, the prevention of beta-amyloid (A beta) deposition and neurotoxicity by small molecule inhibitors of A beta 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 A beta(40) aggregation (expressed as pIC(50)) was found to be correlated with lipophilicity, as assessed by a reversed-phase HPLC method, through a bilinear relationship. The N-1-cyclopropyl derivative 28 was tested in cell-based assays of A beta(42) 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.
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