Salicylanilide diethyl phosphates as cholinesterases inhibitors

Krátký, Martin; Štěpánková, Šárka; Vorčáková, Katarína

doi:10.1016/j.bioorg.2014.11.005

Cited by 19 publications

(13 citation statements)

References 31 publications

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“…To investigate the influence of phosphorus-based substituents, a known scaffold for the inhibition of cholinesterases [8,22,25], of phenolic group on inhibition, we prepared several derivatives of 4-chloro-2-hydroxy- N -[4-(trifluoromethyl)phenyl]benzamide 3k , i.e., the salicylanilide with a moderate activity against AChE and low activity against BuChE. Thus, if the presence of phosphorus-based moiety was beneficial, a drop in IC 50 values would be more significant.…”

Section: Resultsmentioning

confidence: 99%

“…The determination of mechanism of enzyme inhibition was described in detail previously [22]. The inhibitor 5c was evaluated at three different concentrations for each enzyme.…”

Section: Methodsmentioning

confidence: 99%

“…The halogenation ensures sufficient lipophilicity, which should contribute to the passive targeting of CNS. The current study should answer whether parent salicylanilides are able to inhibit AChE and BuChE, how selective and if the intrinsic activity of this scaffold could participate in the inhibition previously described for salicylanilide carbamates and (thio)phosphates [22,23,24,25]. The second goal is focused on the influence of esterification by phosphorus-based acids on enzyme inhibition and selectivity.…”

Section: Introductionmentioning

confidence: 99%

“…We have found salicylanilide O -substituted derivatives with significant activity against AChE and BuChE. Diethyl phosphates act as pseudo-irreversible cholinesterases inhibitors [22], N -phenethyl [23] and N , N -diphenyl carbamates [24] produced clearly favourable BuChE inhibition when compared to other analogues. In addition, salicylanilide diethyl thiophosphates were active, especially against AChE [25]—but there is no study dealing with the inhibition property of parent benzamides with free phenolic group.…”

Section: Introductionmentioning

confidence: 99%

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2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase

et al. 2019

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The development of novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represents a viable approach to alleviate Alzheimer’s disease. Thirty-six halogenated 2-hydroxy-N-phenylbenzamides (salicylanilides) with various substitution patterns and their esters with phosphorus-based acids were synthesized in yields of 72% to 92% and characterized. They were evaluated for in vitro inhibition of AChE from electric eel and BuChE from equine serum using modified Ellman’s spectrophotometric method. The benzamides exhibited a moderate inhibition of AChE with IC50 values in a narrow concentration range from 33.1 to 85.8 µM. IC50 values for BuChE were higher (53.5–228.4 µM). The majority of derivatives inhibit AChE more efficiently than BuChE and are comparable or superior to rivastigmine—an established cholinesterases inhibitor used in the treatment of Alzheimer’s disease. Phosphorus-based esters especially improved the activity against BuChE with 5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl diethyl phosphite 5c superiority (IC50 = 2.4 µM). This derivative was also the most selective inhibitor of BuChE. It caused a mixed inhibition of both cholinesterases and acted as a pseudo-irreversible inhibitor. Several structure-activity relationships were identified, e.g., favouring esters and benzamides obtained from 5-halogenosalicylic acids and polyhalogenated anilines. Both 2-hydroxy-N-phenylbenzamides and esters share convenient physicochemical properties for blood-brain-barrier penetration and thus central nervous system delivery.

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Section: Resultsmentioning

confidence: 99%

“…The determination of mechanism of enzyme inhibition was described in detail previously [22]. The inhibitor 5c was evaluated at three different concentrations for each enzyme.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase

et al. 2019

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“…But, the most conventional theory is “cholinergic hypothesis”. This hypothesis proposes that there is decline in concentration of the neurotransmitter, acetylcholine (Ach) mainly due to the action of cholinesterase enzymes in CNS [ 7 , 8 ]. Therefore, the current therapeutic strategies mainly involve focusing on anti-cholinesterase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

In vitro anti-acetylcholinesterase activity of an aqueous extract of Unicaria tomentosa and in silico study of its active constituents

2016

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Depletion of acetylcholine in the central nervous system (CNS) is responsible for memory loss and cognition deficit. Enzyme acetylcholinesterase (AChE) is responsible for destruction of acetylcholine (Ach) in the brain. Many herbal plant extracts have been investigated for their potential use in the treatment of Alzheimer’s disease (AD) by inhibiting AChE and upregulating the levels of Ach. The current study investigated the anti-acetylcholinesterase (AChE) activity of an aqueous extract of Unicaria tomentosa bark which has not been reported so far in the literature. The in vitro study of an aqueous extract of U. tomentosa showed maximum inhibition of 76.2±0.002 % at 0.4mg/ml of final concentration with an IC50 = 0.112 mg/ml. The mechanism of inhibition was elucidated by kinetic study which showed mixed type of inhibition, this might be due to the presence of various phytoconstituents such as oxindole alkaloids present in an aqueous extract. Based on molecular structure of phytoconstituents obtained from U. tomentosa known from the relevant literature, in-silico molecular docking study was performed against AChE protein to validate the results.

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Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

Dhiman

Singh

2018

IUBMB Life

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Tuberculosis (TB) is a leading cause of mortality and morbidity with an estimated 1.7 billion people latently infected with the pathogen worldwide. Clinically, TB infection presents itself as an asymptomatic infection, which gradually manifests to life threatening disease. The emergence of various drug resistant strains of Mycobacterium tuberculosis and lengthy duration of chemotherapy are major challenges in the field of TB drug development. Hence, there is an urgent need to develop scaffolds that possess a novel mechanism of action, can shorten the duration of therapy, and are active against both drug resistant and susceptible strains. In this review, we will discuss recent progress made in the field of TB drug development with emphasis on screening methods and drug targets from M. tuberculosis. The current review provides insights into mechanism of action of new scaffolds that are being evaluated in various stages of clinical trials. © 2018 IUBMB Life, 70(9):905-916, 2018.

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Salicylanilide diethyl phosphates as cholinesterases inhibitors

Cited by 19 publications

References 31 publications

2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase

2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase

In vitro anti-acetylcholinesterase activity of an aqueous extract of Unicaria tomentosa and in silico study of its active constituents

Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis

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