In vitro reactivation of sarin-inhibited human acetylcholinesterase (AChE) by bis-pyridinium oximes connected by xylene linkers

Acharya, Jyotiranjan; Dubey, D. K.; Srivastava, Ashish Kumar; Raza, S. K.

doi:10.1016/j.tiv.2010.07.024

Cited by 28 publications

(19 citation statements)

References 34 publications

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“…Firstly, the bisquaternary mono-oximes were already found to be satisfactory reactivators of GA- or pesticide-inhibited AChE compared to bis-oximes [ 34 ]. The 4-positioned oxime moiety on the pyridinium scaffold has been used and proposed many times as being optimal for reactivation due to its pKa [ 35 ]. Furthermore, the connecting linkage between heteroarenium rings in the length of 3–4 C-C atoms was highlighted in the case of GA- or pesticide-inhibited AChE [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

et al. 2018

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The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator’s molecule are described.

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Section: Resultsmentioning

confidence: 99%

Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

et al. 2018

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“…DDVP has been reported to exert its primary pharmacological and toxicological effects through the inhibition of acetylcholinesterase, an enzyme required for the transmission of impulses across the cholinergic synapse. 4,5 Other toxicity aspects of DDVP have also been studied extensively. Some articles reported that DDVP affects neutrophil function as well as macrophage and antibody production and generates immunotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic analysis of rat plasma following chronic low-dose exposure to dichlorvos

Yang

Wang

et al. 2012

Hum Exp Toxicol

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This study aims to assess the metabolomic profile and related histopathological outcomes of rat plasma after chronic low-dose exposure to dichlorvos (DDVP). A total of 120 male Wistar rats were treated with 0, 2.4, 7.2, and 21.6 mg/kg of body weight/day DDVP continuously for 24 weeks by drinking water. Rat plasma samples were collected at different time-points to measure the metabolomic profiles by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Liver tissue analysis was performed to correlate histopathological outcome status to plasma metabolomics. Significant changes in some of the metabolites were found in all the treated groups compared with the control group. LysoPC (15:0/0:0), LysoPC (16:0/0:0), LysoPC (17:0/0:0), LysoPC (0:0/18:0), sphingosine, sphinganine, C16 sphinganine, C17 sphinganine, and arachidonic acid were decreased in the treated groups. LysoPE (16:0/0:0) was increased after dosing with DDVP. Histopathological test outcomes coincided with the plasma metabolomic-profile analysis results obtained by UPLC-MS. The livers were damaged following chronic exposure to DDVP. Abnormal changes in some lipids in the plasma, such as LysoPC (0:0/18:0), were closely related to liver dysfunction. Therefore, metabolomic analysis provides the unique advantages of unveiling the mechanisms of DDVP.

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“…It was observed that the calculated pK a values for oximes lie in the range of 7.45-9.85 which is well in agreement with those of known oxime reactivators. pK a values of structurally different xylene linked bispyridinium oximes which were reported by Acharya et al [19,23]. The group has experimentally determined the pK a with the help of Albert and Sergeant method.…”

Section: Resultsmentioning

confidence: 86%

Acid Dissociation Constants and Molecular Descriptors of Some Xylene Linked Bispyridinium Oximes

Singh¹,

Soukup²,

Doležal³

et al. 2015

Mil. Med. Sci. Lett.

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SummaryThe present article is aimed at determination of acid dissociation constants (pK a ), lipophilicity (logP) and hydrogen bond acceptor (HBA) and donor (HBD) counts of some novel xylene-linked bispyridiniumoxime based AChE reactivators. The choice was supported by their use in the therapy of acute intoxication with organophosphorus AChE inhibitors. UV-Vis spectrophotometry has been used to measure experimental pK a values at 27°C, while software Marvin Sketch (chemaxon) has been used to estimate structure based computational pK a , logP values and hydrogen bonding parameters. The results were compared with standard oximes (HI-6 and obidoxime) under similar conditions. All the calculated pK a values lie in the range of 7.45-9.85 which is well in agreement with most of the oxime reactivators studied so far.

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In vitro reactivation of sarin-inhibited human acetylcholinesterase (AChE) by bis-pyridinium oximes connected by xylene linkers

Cited by 28 publications

References 34 publications

Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

Metabolomic analysis of rat plasma following chronic low-dose exposure to dichlorvos

Acid Dissociation Constants and Molecular Descriptors of Some Xylene Linked Bispyridinium Oximes

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