Design, synthesis and evaluation of 3,4-dihydroxybenzoic acid derivatives as antioxidants, bio-metal chelating agents and acetylcholinesterase inhibitors

Friggeri, Laura; Vita, Daniela De; Pandolfi, Fabiana; Tortorella, Silvano; Costi, Roberta; Santo, Roberto Di; Scipione, Luigi

doi:10.3109/14756366.2013.866657

Cited by 11 publications

(6 citation statements)

References 25 publications

(27 reference statements)

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“…The spectrophotometric method of Ellman 16 with minor modifications 17,18 was used to evaluate the inhibition of AChE. Electric eel AChE (AChE, EC 3.1.1.7), acetylthiocholine iodide, 5,5…”

Section: Enzymatic Testsmentioning

confidence: 99%

NewN,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

Vita

Pandolfi

Ornano

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of N,N-dimethylcarbamates containing a N,N-dibenzylamino moiety was synthesized and tested to evaluate their ability to inhibit Acetylcholinesterase (AChE). The most active compounds 4 and 8, showed 85 and 69% of inhibition at 50 mM, respectively. Furthermore, some basic SAR rules were outlined: an alkyl linker of six methylene units is the best spacer between the carbamoyl and dibenzylamino moieties; electron-withdrawal substituents on aromatics rings of the dibenzylamino group reduce the inhibitory power. Compound 4 produces a slow onset inhibition of AChE and this is not due to the carbamoylation of the enzyme, as demonstrated by the time-dependent inhibition assay of AChE with compound 4 and by MALDI-TOF MS analysis of trypsinized AChE inhibited by compound 4. Instead, compound 4 could act as a slow-binding inhibitor of AChE, probably because of its high conformational freedom due to the linear alkyl chain.

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“…The spectrophotometric method of Ellman 16 with minor modifications 17,18 was used to evaluate the inhibition of AChE. Electric eel AChE (AChE, EC 3.1.1.7), acetylthiocholine iodide, 5,5…”

Section: Enzymatic Testsmentioning

confidence: 99%

NewN,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

Vita

Pandolfi

Ornano

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Cholinesterase inhibitory properties of caffeic acid and chlorogenic acid, 3,4-dihydroxybenzoic acid derivatives, some hydroxycinnamic acids, pyrogallol were reported. [25][26][27][28] So, in this study we have evaluated acetylcholinesterase inhibitory activities of 1,2,4-benzenetriol, 4-methylcatechol, piceatannol and hydroxychavicol. Hydroxychavicol is an abundant phenolic compound detected in the betel leaves.…”

Section: Discussionmentioning

confidence: 99%

Anti-Alzheimer’s Potential of Different Varieties of Piper betle Leaves and Molecular Docking Analyses of Metabolites

Debnath

Das

et al. 2021

FRA

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Introduction: Acetylcholinesterase inhibitors are used to prevent symptoms of Alzheimer's disease which is initiated due to oxidative stress. Piper betle L. is a tropical evergreen perennial vine whose leaves are widely consumed as masticator in Asia and has medicinal properties. Objectives: The present study is aimed to investigate acetylcholinesterase inhibitory property of methanolic extracts of different varieties of Piper betle leaves and chemometrically identify different bioactive ingredients in vitro and in silico. Materials and Methods: Methanol extracts of the leaves collected in February and October from eight varieties of P. betle (Chhanchi, Bagerhati, Manikdanga, Kalibangla, Bangla, Ghanagete, Meetha and Haldi) were studied for acetylcholinesterase inhibitory properties. Chemical components were analyzed by Gas Chromatography -Mass spectrometry and High Performance Thin Layer Chromatography. Active metabolites were identified chemometrically. The activities were proved in vitro and in silico. Results: All the extracts inhibited acetylcholinesterase. Statistical analysis suggested that several phenolic compounds were correlated to anti-cholinesterase activity. Piceatannol, hydroxychavicol, benzene-1,2,4-triol, and 4-methylcatechol are reported here to have such enzyme inhibitory properties. These four small molecules were further subjected to molecular docking analysis to explore their binding mechanism with the acetylcholinesterase enzyme. All the four small molecules are found to interact with the targeted enzyme in similar fashion like the molecular interactions observed for the standard inhibitor, Donepezil, at the active site of acetylcholiesterase. Conclusion: Thus, consumption of P. betle leaves may have a beneficial effect in the prevention and treatment of this neurodegenerative disease.

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“…The (Z)-acrylonitrile analog 112 ( Figure 22, Table 6) bearing trimethoxy group showed efficient AChE inhibition, with IC 50 values of 0.20 μM in human [176] where the methoxy group at the 4-position of phenyl ring has been considered essential for AChE inhibition. The 3,4-dihydroxybenzoic acid derivative 113 ( Figure 22) found to be highly selective non-competitive or mixed type of eeAChE inhibitor with low 1.5 μM K i values and showed very good metal (Fe +2 , Cu +2 , Zn +2 ) chelating properties [177]. The reported molecule also exhibited good antioxidant activity as remarkable radical scavenging ability (EC 50 = 0.12 μM) which was higher than trolox (EC 50 = 0.15 μM) in 2,2-Diphenyl-2-Picrylhydrazyl (DPPH) assay.…”

Section: Novel Small Moleculesmentioning

confidence: 99%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

AND

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Alzheimer's Disease (AD) is characterized by the loss of memory and learning ability in elderly patients affecting large population worldwide. The enzyme Acetylcholinesterase (AChE), (E.C.3.1.1.7) plays a major role in the hydrolysis of the released neurotransmitter acetylcholine. Most of the clinically used drugs to treat AD are Acetylcholinesterase Inhibitors (AChEIs). These drugs can provide symptomatic benefits only and suffer with loss of therapeutic potential with time. Therefore, there is an urgent need of novel cholinesterase inhibitors with wider therapeutic window for the treatment of AD. The strategies targeting the AChE enzyme along with other target(s) like Butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals (Cu 2+ , Zn 2+ , or Fe 2+), antioxidant properties and free radical scavenging capacity have been mainly focused in the last five years. A number of hybrid molecules incorporating sub-structures with the desired well-established pharmacological profile into a single scaffold have been investigated. The main sub structures used in developing these molecules are derived from diverse chemical classes such as acridine, quinoline, carbamates, huperzine and other heterocyclic analogs. It has been followed by optimization of activity through structural modifications of the prototype molecules for developing the Structure Activity Relationship (SAR). This has led to the development of novel molecules with desired AChE inhibitory activity along with other desirable pharmacological properties. This review summarizes the current therapeutic strategies for the development of these AChEI in the last seven years.

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Design, synthesis and evaluation of 3,4-dihydroxybenzoic acid derivatives as antioxidants, bio-metal chelating agents and acetylcholinesterase inhibitors

Cited by 11 publications

References 25 publications

NewN,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

NewN,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation

Anti-Alzheimer’s Potential of Different Varieties of Piper betle Leaves and Molecular Docking Analyses of Metabolites

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

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