Tacrine-hydroxamate derivatives as multitarget-directed ligands for the treatment of Alzheimer’s disease: Design, synthesis, and biological evaluation

Xu, Ana; He, Feng; Zhang, Xiangna; Li, Xiaoyang; Ran, Yingying; Wei, Chao; Chou, C. James; Zhang, Rui; Wu, Jingde

doi:10.1016/j.bioorg.2020.103721

Cited by 27 publications

(14 citation statements)

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“…An acridine-based HDAC inhbitor, designed as a multi-target agent against HDAC and acetylcholine esterase showed selective inhbition of HDAC6 and strong activity against Ab-aggregation (Tseng et al, 2020). A new tacrine-hydroxamate pan HDACi exhibited inhibitory activity on Ab1-42 selfaggregation as well as disaggregation activity on pre-formed Ab fibrils, the pathological markers of AD (Xu et al, 2020). Knockout of HDAC2 in mice leads to cognitive enhancement, and inhbitors of HDAC2 have shown potential as therapeutics for restotation of memory affected due to AD (Poplawski et al, 2020).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

2020

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Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.

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Section: Alzheimer's Diseasementioning

confidence: 99%

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

2020

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“…A possible way to extend the therapeutic range of ChE inhibitors, thereby producing a more significant reduction in AD symptoms, is to combine their anticholinesterase action with other activities within a single drug molecule, thus generating multitarget directed ligands (MTDL), which feature a number of advantages over drug combinations, such as the lack of drug–drug interactions and simpler development, manufacturing, and intellectual property issues, among others. − Such compounds should not only inhibit ChE activity but also promote other actions, such as inhibition of Aβ production ( e.g. , through inhibition of BACE-1) and self-aggregation, or antioxidant activities. − In practice, such MTDLs are usually designed by covalently linking a known ChE inhibitor to a second pharmacophoric moiety that can afford additional biological actions arising from the modulation of another key target in AD pathophysiology, such as oxidative stress, among others. − …”

Section: Introductionmentioning

confidence: 99%

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

et al. 2020

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The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.

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“…[ 37,38 ] The 4BDS protein has been even widely adopted to study the interaction of bioactive ligands and hBChE by the scientific community to date. [ 39–42 ]…”

Section: Resultsmentioning

confidence: 99%

In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids

Faudzi

Leong

Auwal

et al. 2020

Archiv der Pharmazie

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A new series of pyrazole, phenylpyrazole, and pyrazoline analogs of diarylpentanoids (excluding compounds 3a, 4a, 5a, and 5b) was pan‐assay interference compounds‐filtered and synthesized via the reaction of diarylpentanoids with hydrazine monohydrate and phenylhydrazine. Each analog was evaluated for its anti‐inflammatory ability via the suppression of nitric oxide (NO) on IFN‐γ/LPS‐activated RAW264.7 macrophage cells. The compounds were also investigated for their inhibitory capability toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), using a modification of Ellman's spectrophotometric method. The most potent NO inhibitor was found to be phenylpyrazole analog 4c, followed by 4e, when compared with curcumin. In contrast, pyrazole 3a and pyrazoline 5a were found to be the most selective and effective BChE inhibitors over AChE. The data collected from the single‐crystal X‐ray diffraction analysis of compound 5a were then applied in a docking simulation to determine the potential binding interactions that were responsible for the anti‐BChE activity. The results obtained signify the potential of these pyrazole and pyrazoline scaffolds to be developed as therapeutic agents against inflammatory conditions and Alzheimer's disease.

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Tacrine-hydroxamate derivatives as multitarget-directed ligands for the treatment of Alzheimer’s disease: Design, synthesis, and biological evaluation

Cited by 27 publications

References 50 publications

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

In silico studies, nitric oxide, and cholinesterases inhibition activities of pyrazole and pyrazoline analogs of diarylpentanoids

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