Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer’s disease

Singh, Yash Pal; Shankar, Gauri; Jahan, Shagufta; Singh, Gireesh Kumar; Kumar, Navneet; Barik, Atanu; Upadhyay, Prabhat; Singh, Lalji; Kamble, Kajal; Tiwari, Sanjay; Garg, Prabha; Gupta, Sarika; Modi, Gyan

doi:10.1016/j.bmc.2021.116385

Cited by 13 publications

(21 citation statements)

References 45 publications

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“…The experiment was performed following the protocol from our publication. 57 Briefly, in a 96-well plate, 10 000 cells/well were seeded and incubated overnight. The concentration of H 2 O 2 was determined based on the UV method, and thereafter, the cells were treated with different concentrations (100, 200, 400, 600, and 800 μM) of H 2 O 2 for 24 h except for the control wells (without any treatment).…”

Section: Methodsmentioning

confidence: 99%

“…After determination of the concentration of H 2 O 2 and time point that can produce approximately 50% cell viability, the neuroprotective effect of different concentrations of F24 was evaluated following the protocol in our earlier publication. 57 Briefly, SH-SY5Y cells were pretreated with F24 or DPZ at five different concentrations followed by co-incubation with 600 μM H 2 O 2 for an additional 24 h. Cells in the control wells were grown without any treatment.…”

Section: Methodsmentioning

confidence: 99%

“…The experiment was performed following the protocol from our publication . Briefly, in a 96-well plate, 10 000 cells/well were seeded and incubated overnight.…”

Section: Materials and Methodsmentioning

confidence: 99%

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Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid β Induced Neurotoxicity in Alzheimer’s Disease Models

Singh

Kumar

Priya

et al. 2021

ACS Chem. Neurosci.

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The pathological hallmarks of Alzheimer’s disease (AD) are manifested as an increase in the level of oxidative stress and aggregation of the amyloid-β protein. In vitro, in vivo, and in silico experiments were designed and carried out with multifunctional cholinergic inhibitor, F24 (EJMC-7a) to explore its neuroprotective effects in AD models. The neuroprotection ability of F24 was tested in SH-SY5Y cells, a widely used neuronal cell line. The pretreatment and subsequent co-treatment of SH-SY5Y cells with different doses of F24 was effective in rescuing the cells from H2O2 induced neurotoxicity. F24 treated cells were found to be effective in the reduction of cellular reactive oxygen species, DNA damage, and Aβ1–42 induced neurotoxicity, which validated its neuroprotective effectiveness. F24 exhibited efficacy in an in vivo Drosophila model by rescuing eye phenotypes from degeneration caused by Aβ toxicity. Further, computational studies were carried out to monitor the interaction between F24 and Aβ1–42 aggregates. The computational studies corroborated our in vitro and in vivo studies suggesting Aβ1–42 aggregation modulation ability of F24. The brain entry ability of F24 was studied in the parallel artificial membrane permeability assay. Finally, F24 was tested at doses of 1 and 2.5 mg/kg in the Morris water maze AD model. The neuroprotective properties shown by F24 strongly suggest that multifunctional features of this molecule provide symptomatic relief and act as a disease-modifying agent in the treatment of AD. The results from our experiments strongly indicated that natural template-based F24 could serve as a lead molecule for further investigation to explore multifunctional therapeutic agents for AD management.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid β Induced Neurotoxicity in Alzheimer’s Disease Models

Singh

Kumar

Priya

et al. 2021

ACS Chem. Neurosci.

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“…As previously noted in earlier studies, binding of ligands, namely DPZ, results in a considerable reduction in the RMSD value. [26,27] During the last few ns of simulations, the RMSD uctuation of AChE decreased in the presence of 6a. There is signi cant decrease in average RMSD value of AChE in presence of both ligands.…”

Section: Analysis Of Structural Stability Compactness and Binding Fre...mentioning

confidence: 97%

Design, Synthesis, and biological evaluation of pyrazolo-benzothiazole derivatives as a potential therapeutic agent for the treatment of Alzheimer’s disease

et al. 2022

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Alzheimer's disease (AD) is a neurodegenerative age related brain disease which diminishes learning and memory.Two common cholinesterases (ChEs), rst acetylcholinesterase (AChE) and second one butyrylcholinesterase (BChE) are the main targets to treat this disease. In the current paper, six novel pyrazolo-benzothiazole analogs were systematically planned, synthesized, and biological tested for their ChEs activities, antioxidant, enzyme kinetic, self induced Aβ modulation, PAMPA-BBB, and docking and molecular simulation study. Among all derivatives,4a bearing 3,4-dimethoxypyrazolo-benzothiazole molecules was the potential inhibitor of AChE (IC 50 = 8.69 ± 0.42 µM), Aβ modulator and good antioxidant. Docking studies also clearly revealed that compound 4a t into the active sites of hAChE.

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“…The exact pathophysiology of AD is still under investigation. However, some hypotheses proposed that the loss of cholinergic transmission, Aβ toxicity, oxidative stress, tau hyperphosphorylation, and metal ion hypothesis are the major pathological factors involved in AD (Figure 1; Leng et al, 2016;Singh et al, 2019Singh et al, , 2022Singh, Shankar et al, 2021;Srivastava et al, 2021). The cholinergic hypothesis is one of the oldest hypothesis of AD described in 1976.…”

Section: Introductionmentioning

confidence: 99%

Berberine derivatives as inhibitors of acetylcholinesterase: A systematic review

Singh,

Kumar

2023

Chem Biol Drug Des

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Alzheimer's disease (AD) is a chronic age‐related neurodegenerative brain disorder characterized by the impairment of memory accompanied by worsening of thinking ability of an individual. The exact pathophysiology of AD is not fully understood. However low level of the neurotransmitter named acetylcholine (ACh), aggregation of Aβ peptide into toxic Aβ plaque, hyperphosphorylation of tau, bio‐metal imbalance, and oxidative stress are the main hallmarks of this disease. Due to the complex pathophysiology of AD, no specific treatment is available in the market, and treatment is only limited to the symptomatic relief. So, there is an urgent need for the development of new drug candidate, which can have disease‐modifying effect and improve learning and memory in AD patient. Therefore, berberine‐based multifunction compounds with potential cholinesterase inhibitory properties were reviewed in this article. Structure–activity relationship (SAR) and biological activity provide highlights on the new derivatives used for the management of AD.

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Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer’s disease

Cited by 13 publications

References 45 publications

Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid β Induced Neurotoxicity in Alzheimer’s Disease Models

Exploration of Neuroprotective Properties of a Naturally Inspired Multifunctional Molecule (F24) against Oxidative Stress and Amyloid β Induced Neurotoxicity in Alzheimer’s Disease Models

Design, Synthesis, and biological evaluation of pyrazolo-benzothiazole derivatives as a potential therapeutic agent for the treatment of Alzheimer’s disease

Berberine derivatives as inhibitors of acetylcholinesterase: A systematic review

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