Tridentate N-Acylhydrazones as Moderate Ligands for the Potential Management of Cognitive Decline Associated With Metal-Enhanced Neuroaggregopathies

Cukierman, Daphne S.; Rey, Nicolás A.

doi:10.3389/fneur.2022.828654

Cited by 7 publications

(4 citation statements)

References 36 publications

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“…For example, 1-methyl-1 H -imidazole-2-carboxaldehyde isonicotinoyl hydrazone (X1INH) was recently reported to attenuate abnormal Cu-α-synuclein interactions and to lessen protein aggregation . Several other examples have been recently reviewed. − …”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s Drug PBT2 Interacts with the Amyloid β 1–42 Peptide Differently than Other 8-Hydroxyquinoline Chelating Drugs

et al. 2022

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Although Alzheimer’s disease (AD) was first described over a century ago, it remains the leading cause of age-related dementia. Innumerable changes have been linked to the pathology of AD; however, there remains much discord regarding which might be the initial cause of the disease. The “amyloid cascade hypothesis” proposes that the amyloid β (Aβ) peptide is central to disease pathology, which is supported by elevated Aβ levels in the brain before the development of symptoms and correlations of amyloid burden with cognitive impairment. The “metals hypothesis” proposes a role for metal ions such as iron, copper, and zinc in the pathology of AD, which is supported by the accumulation of these metals within amyloid plaques in the brain. Metals have been shown to induce aggregation of Aβ, and metal ion chelators have been shown to reverse this reaction in vitro. 8-Hydroxyquinoline-based chelators showed early promise as anti-Alzheimer’s drugs. Both 5-chloro-7-iodo-8-hydroxyquinoline (CQ) and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2) underwent unsuccessful clinical trials for the treatment of AD. To gain insight into the mechanism of action of 8HQs, we have investigated the potential interaction of CQ, PBT2, and 5,7-dibromo-8-hydroxyquinoline (B2Q) with Cu(II)-bound Aβ(1–42) using X-ray absorption spectroscopy (XAS), high energy resolution fluorescence detected (HERFD) XAS, and electron paramagnetic resonance (EPR). By XAS, we found CQ and B2Q sequestered ∼83% of the Cu(II) from Aβ(1–42), whereas PBT2 sequestered only ∼59% of the Cu(II) from Aβ(1–42), suggesting that CQ and B2Q have a higher relative Cu(II) affinity than PBT2. From our EPR, it became clear that PBT2 sequestered Cu(II) from a heterogeneous mixture of Cu(II)Aβ(1–42) species in solution, leaving a single Cu(II)Aβ(1–42) species. It follows that the Cu(II) site in this Cu(II)Aβ(1–42) species is inaccessible to PBT2 and may be less solvent-exposed than in other Cu(II)Aβ(1–42) species. We found no evidence to suggest that these 8HQs form ternary complexes with Cu(II)Aβ(1–42).

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Section: Introductionmentioning

confidence: 99%

Alzheimer’s Drug PBT2 Interacts with the Amyloid β 1–42 Peptide Differently than Other 8-Hydroxyquinoline Chelating Drugs

et al. 2022

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“…[35] Our group has been developing and testing new metallophores for over a decade, having pioneered that the chemical class of N-acylhydrazones compose a set of promising agents for the tentative therapeutic management of metal-enhanced aggregopathies. [36] Our lead compound, phenol-containing 8hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone, [37] INHHQ (Scheme 1A), competes with both AD-related amyloid-β peptide (Aβ) [38] and PD's protein α-synuclein (α-Syn) [39] for the in vitro binding of metal ions such as zinc(II), and the redox pair copper(I)/copper(II). This aroylhydrazone has been the subject of recently granted patents in the United States.…”

Section: Introductionmentioning

confidence: 99%

Cardiotoxicity and ROS Protection Assessment of three Structure‐Related N‐Acylhydrazones with Potential for the Treatment of Neurodegenerative Diseases

Helena,

De Falco,

Cukierman

et al. 2024

Chemistry & Biodiversity

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The senescence process is associated with accumulated oxidative damage and increased metal concentration in the heart and brain. Besides, abnormal metal‐protein interactions have also been linked with the development of several conditions, including Alzheimer’s and Parkinson’s diseases. Over the years we have described a series of structure‐related compounds with different activities towards models of such diseases. In this work, we evaluated the potential of three N‐acylhydrazones (INHHQ: 8‐hydroxyquinoline‐2‐carboxaldehyde isonicotinoyl hydrazone, HPCIH: pyridine‐2‐carboxaldehyde isonicotinoyl hydrazone and X1INH: 1‐methyl‐1H‐imidazole‐2‐carboxaldehyde isonicotinoyl hydrazone) to prevent oxidative stress in cellular models, with the dual intent of being active on this pathway and also to confirm their lack of cardiotoxicity as an important step in the drug development process, especially considering that the target population often presents cardiovascular comorbidity. The 8‐hydroxyquinoline‐contaning compound, INHHQ, exhibits a significant cardioprotective effect against hydrogen peroxide and a robust antioxidant activity. However, this compound is the most toxic to the studied cell models and seems to induce oxidative damage on its own. Interestingly, although not possessing a phenol group in its structure, the new‐generation 1‐methylimidazole derivative X1INH showed a cardioprotective tendency towards H9c2 cells, demonstrating the importance of attaining a compromise between activity and intrinsic cytotoxicity when developing a drug candidate.

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“…N-acylhydrazones showed strong iron-chelating properties and, therefore, were originally suggested as drug candidates for the treatment of iron-overload diseases [ 26 ]. In particular, they were able to moderately bind biometals, and this affinity and specificity could be modified by the appropriate selection of the aldehyde precursor and substituents [ 27 ]. For example, in the well-studied N-acylhydrazone INHHQ, it has been shown that, in healthy Wistar rats, N-acylhydrazone was capable of crossing the blood–brain barrier.…”

Section: Introductionmentioning

confidence: 99%

New Indole-3-Propionic Acid and 5-Methoxy-Indole Carboxylic Acid Derived Hydrazone Hybrids as Multifunctional Neuroprotectors

et al. 2023

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In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 μM) and IC50 > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H2O2-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders.

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Tridentate N-Acylhydrazones as Moderate Ligands for the Potential Management of Cognitive Decline Associated With Metal-Enhanced Neuroaggregopathies

Cited by 7 publications

References 36 publications

Alzheimer’s Drug PBT2 Interacts with the Amyloid β 1–42 Peptide Differently than Other 8-Hydroxyquinoline Chelating Drugs

Alzheimer’s Drug PBT2 Interacts with the Amyloid β 1–42 Peptide Differently than Other 8-Hydroxyquinoline Chelating Drugs

Cardiotoxicity and ROS Protection Assessment of three Structure‐Related N‐Acylhydrazones with Potential for the Treatment of Neurodegenerative Diseases

New Indole-3-Propionic Acid and 5-Methoxy-Indole Carboxylic Acid Derived Hydrazone Hybrids as Multifunctional Neuroprotectors

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