New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease

Jalili‐Baleh, Leili; Nadri, Hamid; Moradi, Alireza; Bukhari, Syed Nasir Abbas; Shakibaie, Mojtaba; Jafari, Mandana; Golshani, Mostafa; Moghadam, Farshad Homayouni; Firoozpour, Loghman; Asadipour, Ali; Emami, Saeed; Khoobi, Mehdi; Foroumadi, Alireza

doi:10.1016/j.ejmech.2017.07.072

Cited by 54 publications

(23 citation statements)

References 38 publications

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“…Inhibition of Aβ1-42 self-aggregation was measured by ThT fluorescence assay. The details of the method were reported in our previous study [ 45 ]. To study Aβ 42 aggregation inhibition, a reported method, based on the fluorescence emission of ThT was followed.…”

Section: Methodsmentioning

confidence: 99%

“…The final concentrations of Aβ (dissolved in DMSO and diluted 0.215 M sodium phosphate buffer, pH 8), AChE (dissolved in 0.215 M sodium phosphate buffer, pH 8.0), and the test compound are 200 µM, 2 µM and 100 µM, respectively. After co-incubation, 20 µL of the mixed solution was diluted to a final volume of 2 mL with ThT (1.5 µM in 50 mM glycine–NaOH buffer, pH 8.5) and the absorbance was measured with a multi-mode plate reader at the excitation and emission wavelength of λex = 450 nm and λem = 485 nm, respectively [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

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Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

et al. 2020

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To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

et al. 2020

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“…The co-incubation experiment of Aβ 1–42 with AChE was performed by ThT bioassay according to a reported protocol [ 35 ]. HFIP pre-treated Aβ 1–42 (GL Biochem Ltd., shanghai, China) was dissolved in DMSO to make a 200 µM stock solution.…”

Section: Methodsmentioning

confidence: 99%

Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors

et al. 2018

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A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aβ aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer’s disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development.

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“…Acetylcholinesterase (AchE) is a polymorphic enzyme commonly known for its cholinergic action that stops cholinergic signaling in the brain by hydrolyzing acetylcholine to choline and acetate [23]. The expression of AchE is closely correlated with the neuroinflammatory response and neurological dysfunction [24,25]. Studies have shown that the expression of AchE is increased after hypoxia-ischemia (HI) in newborn rats, and further research has confirmed that the inhibition of the AchE receptor reduces brain damage after HI [26].…”

Section: Fa and Lna-mir-9 Protected Against Synaptic Marker Loss Indumentioning

confidence: 99%

MicroRNA-9 Mediated the Protective Effect of Ferulic Acid on Hypoxic-Ischemic Brain Injury in Neonatal Rats

Yao

Yang

et al. 2020

Preprint

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Abbreviations: HIBD, hypoxic-ischemic brain damage; HI, hypoxia-ischemia; FA, ferulic acid; SF, sodium ferulic; qRT-PCR, quantitative real-time PCR; AchE, acetylcholinesterase; PSD-95, postsynaptic density protein-95; miR-9, microRNA-9; LNA-miR-9: locked nucleic acid-miR-9; DG, dentate gyrus.Abstract--Neonatal hypoxic-ischemic brain damage (NHIBD) leads to cognitive and memory impairments, and there is no effective clinical treatment. Ferulic acid (FA)is found within members of the genus Angelica, reportedly shows protective effects on neuronal damage; however, the mechanism of the protective effects of FA on rats following NHIBD remains unclear. Using the Morris water maze task, we herein found that the impairment of spatial memory formation in adult rats exposed to NHIBD was significantly reversed by FA treatment and the administration of LNA-miR-9. RT-PCR analyses revealed that miRNA-9 was significantly increased in the hippocampus of neonatal rats and neuronal PC12 cells following NHIBD and that FA and LNA-miR-9 both inhibited the expression of miRNA-9, suggesting that the therapeutic effect of FA was mainly attributed to the inhibition of miRNA-9 expression. Indeed, the silencing of miR-9 by LNA-miR-9 or FA similarly attenuated neuronal damage and cerebral atrophy in the rat hippocampus after NHIBD, which was consistent with the restored expression levels of brain-derived neurotrophic factor (BDNF). Therefore, FA treatment may protect against neuronal death through the inhibition of miRNA-9 induction in the rat hippocampus following hypoxic-ischemic damage.

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New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease

Cited by 54 publications

References 38 publications

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors

MicroRNA-9 Mediated the Protective Effect of Ferulic Acid on Hypoxic-Ischemic Brain Injury in Neonatal Rats

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