Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer’s disease

Shrivastava, Sushant K.; Sinha, Saurabh; Srivastava, Pavan; Tripathi, Prem Prakash; Sharma, Piyoosh; Tripathi, Manish Kumar; Tripathi, Avanish; Choubey, Priyanka Kumari; Waiker, Digambar Kumar; Aggarwal, Lalit Mohan; Dixit, Manish; Kheruka, Subhash Chand; Gambhir, Sanjay; Shankar, Sharmila; Srivastava, Rakesh K.

doi:10.1016/j.bioorg.2018.10.009

Cited by 48 publications

(27 citation statements)

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“…Diethylthiophosphoric acid is a part of the aminobenzoate degradation pathway. Derivatives of aminobenzoic acid may have potential as drugs to inhibit acetylcholinesterase, thereby ameliorating the acetylcholine deficit present in AD (Shrivastava et al 2019). 11,12-DHET derives from oxidation of arachidonic acid, a well-known precursor activated during inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Cross-species metabolomic analysis of DDT and Alzheimer’s disease-associated tau toxicity

Kalia

et al. 2021

Preprint

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Background. The formation of hyperphosphorylated tau (p-tau) protein tangles in neurons is a pathological marker of Alzheimer's disease (AD). Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with an increased risk of AD. Objectives. To determine if there was a connection between DDT exposure and tau toxicity we investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans. In addition, we examined the association between p-tau protein and metabolism in a human population study and in a transgenic C. elegans strain neuronally expressing a mutant tau protein fragment that is prone to aggregation. Methods. In the human population study, we used a metabolome-wide association framework to determine the association between p-tau measured in the cerebrospinal fluid (CSF) and metabolomic features measured in both plasma (n = 142) and CSF (n = 78) using high-resolution metabolomics (HRM). Using the same HRM method, we determined changes in metabolomic features in the transgenic C. elegans strain compared to its control strain. Metabolites associated with p-tau in both species were analyzed for overlap. We also examined the effect of DDT and aggregating tau protein on growth, swim behavior, mitochondrial function, metabolism, learning, and lifespan in C. elegans. Results. Plasma and CSF-derived features associated with p-tau level were related to drug, amino acid, fatty acid, and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of aggregating tau protein on growth and basal respiration. In the presence of aggregating tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Developmental exposure to DDT blunted the lifespan reduction caused by aggregating tau protein. Conclusion. The model organism C. elegans can complement human studies by providing a means to study mechanisms of environmental toxicants. Specifically, our C. elegans data show that DDT exposure and tau protein aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of tau protein aggregation providing a plausible explanation for the observed human associations.

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Section: Discussionmentioning

confidence: 99%

Cross-species metabolomic analysis of DDT and Alzheimer’s disease-associated tau toxicity

Kalia

et al. 2021

Preprint

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“…Traditional approaches based on cholinergic dysfunction have been highly utilised for treatment of AD [2]. Current FDA approved drugs include donepezil, rivastigmine, galantamine and memantine of which the first three drugs are acetylcholine esterase inhibitors, while memantine targets the N-methyl-D-aspartic receptor (NMDAR) [92,93]. Damage of cholinergic neuronal cells leading to the reduced levels of acetylcholine, a neurotransmitter involved in cognition and synapsis, has been found to be associated with AD [94].…”

Section: Current Therapeutic Approaches Only Target Symptoms Of Admentioning

confidence: 99%

Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease

Dhakal

Kushairi

Phan

et al. 2019

IJMS

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Ageing is an inevitable fundamental process for people and is their greatest risk factor for neurodegenerative disease. The ageing processes bring changes in cells that can drive the organisms to experience loss of nutrient sensing, disrupted cellular functions, increased oxidative stress, loss of cellular homeostasis, genomic instability, accumulation of misfolded protein, impaired cellular defenses and telomere shortening. Perturbation of these vital cellular processes in neuronal cells can lead to life threatening neurological disorders like Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, Lewy body dementia, etc. Alzheimer’s Disease is the most frequent cause of deaths in the elderly population. Various therapeutic molecules have been designed to overcome the social, economic and health care burden caused by Alzheimer’s Disease. Almost all the chemical compounds in clinical practice have been found to treat symptoms only limiting them to palliative care. The reason behind such imperfect drugs may result from the inefficiencies of the current drugs to target the cause of the disease. Here, we review the potential role of antioxidant polyphenolic compounds that could possibly be the most effective preventative strategy against Alzheimer’s Disease.

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“…In the recent period, researchers started to investigate the potential active compounds from herbal sources, which would not cause these adverse effects (Howes and Houghton, 2003, Hu et al, 2013, Lasano et al, 2019). In the present study, the potential of plant extracts for controlling diabetes and Alzheimer’s disease was determined with in vitro methods by inhibiting the key enzymes (α-amylase, α-glucasidase for diabetes and cholinesterases for Alzeimer’ disease) playing role in the management of these disorders (Figueiredo-González et al, 2019, Shrivastava et al, 2019). The enzyme inhibition activity results of plant extracts are presented in Table 4.…”

Section: Resultsmentioning

confidence: 99%

Antibacterial, antioxidant and enzyme inhibition activity capacities of Doronicum macrolepis (FREYN&SINT): An endemic plant from Turkey

Özcan

2020

Saudi Pharmaceutical Journal

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In the present study, the antioxidant, enzyme inhibition (α-amylase, α-glucosidase, and cholinesterase) and antimicrobial (MIC) activities of three different solvent (ethanol, methanol, or ethyl acetate) extracts of stem, root, and flower of Doronicum macrolepis plant were investigated. In addition to this, the chemical composition and the antimicrobial activity of the essential oil were determined. Antioxidant activity was detected using ABTS and DPPH assays. Antimicrobial activity evaluated by microdilution method against to nineteen microorganisms. Also, enzyme inhibition activities were determined by colorimetric methods. Essential oil of the plant extracted by hydrodistilation and characterized using GC/MS. The antioxidant properties of the flower were determined to be higher than those of the other segments of this plant. Moreover, the total phenolic and flavonoid contents were also found to be higher in the flower parts. The highest enzyme inhibition activity was observed to be α-amylase (221.54 mmol ACAE/g extract) in flower ethylacetate extract, α-glucosidase (15.32 mmol ACAE/g extract) in flower ethanol extract, and cholinesterase (AChE: 2.4 and BChE: 22.35 mg GALE/g extract) in stem ethylacetate extract. Besides them, the antimicrobial activity of the essential oil was found to be higher than the extracts. It showed a high level of inhibition especially on E. coli at 4 µg/ml concentration. Moreover, remarkable inhibition was observed for two candida strains tested. In conclusion, the results suggest that, because of its bioactivity including the antioxidant, antimicrobial, and enzyme inhibition properties, the D. macrolepis can be accepted as a promising and natural source for the industrial applications. The present study is the first study, in which the bioactive components and the antioxidant, antimicrobial, and enzyme inhibition properties of endemic D. macrolepis plant were determined.

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Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer’s disease

Cited by 48 publications

References 50 publications

Cross-species metabolomic analysis of DDT and Alzheimer’s disease-associated tau toxicity

Cross-species metabolomic analysis of DDT and Alzheimer’s disease-associated tau toxicity

Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease

Antibacterial, antioxidant and enzyme inhibition activity capacities of Doronicum macrolepis (FREYN&SINT): An endemic plant from Turkey

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