Insights into Structure-Activity Relationships of 3-Arylhydrazonoindolin-2-One Derivatives for Their Multitarget Activity on β-Amyloid Aggregation and Neurotoxicity.
Rosa PurgatorioModesto de CandiaAnnalisa De PalmaFrancesco De SantisLeonardo PisaniFrancesco CampagnaSaverio CellamareCosimo Damiano AltomareMarco CattoPublished in: Molecules (Basel, Switzerland) (2018)
Despite the controversial outcomes of clinical trials executed so far, the prevention of β-amyloid (Aβ) deposition and neurotoxicity by small molecule inhibitors of Aβ 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 Aβ40 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 Aβ42 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.
Keyphrases
- hydrogen peroxide
- small molecule
- oxidative stress
- clinical trial
- nitric oxide
- structure activity relationship
- ms ms
- single cell
- high throughput
- ionic liquid
- cognitive decline
- randomized controlled trial
- metabolic syndrome
- type diabetes
- high performance liquid chromatography
- mass spectrometry
- atomic force microscopy
- stem cells
- phase ii
- signaling pathway
- diabetic rats
- protein protein
- adipose tissue
- single molecule
- drug induced
- study protocol
- weight loss
- double blind
- visible light