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Molecules 2018, 23(7), 1544; https://doi.org/10.3390/molecules23071544

Insights into Structure-Activity Relationships of 3-Arylhydrazonoindolin-2-One Derivatives for Their Multitarget Activity on β-Amyloid Aggregation and Neurotoxicity

1
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, via E. Orabona 4, I-70125 Bari, Italy
2
Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari “Aldo Moro”, via E. Orabona 4, I-70125 Bari, Italy
*
Author to whom correspondence should be addressed.
Received: 11 May 2018 / Revised: 18 June 2018 / Accepted: 24 June 2018 / Published: 26 June 2018
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Abstract

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. View Full-Text
Keywords: beta-amyloid aggregation inhibitors; indolin-2-ones; Alzheimer’s disease; quantitative structure-activity relationships; multitarget activity beta-amyloid aggregation inhibitors; indolin-2-ones; Alzheimer’s disease; quantitative structure-activity relationships; multitarget activity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Purgatorio, R.; de Candia, M.; De Palma, A.; De Santis, F.; Pisani, L.; Campagna, F.; Cellamare, S.; Altomare, C.D.; Catto, M. Insights into Structure-Activity Relationships of 3-Arylhydrazonoindolin-2-One Derivatives for Their Multitarget Activity on β-Amyloid Aggregation and Neurotoxicity. Molecules 2018, 23, 1544.

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