Oxyaniliniums as acetylcholinesterase inhibitors for the reversal of neuromuscular block

Grove, Simon J. A.; Kaur, Jaspreet; Muir, Alan W.; Pow, Eleanor; Tarver, Gary J.; Zhang, Ming‐Qiang

doi:10.1016/s0960-894x(01)00703-x

Cited by 18 publications

(21 citation statements)

References 6 publications

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“…The neostigmine conjugates ( 22 , 25 and 28 ) were also accessed by EDC∙HCl/DMAP coupling of an NSAID to 3‐(dimethylamino)phenol, which was synthesized using the method of Simon et al . (), followed by quaternization.…”

Section: Methodsmentioning

confidence: 97%

Investigation of anticholinergic and non‐steroidal anti‐inflammatory prodrugs which reduce chemically induced skin inflammation

Young

Fabio

Huang

et al. 2011

J of Applied Toxicology

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As part of a continuous effort to develop efficient countermeasures against sulfur mustard injuries, several unique NSAID prodrugs have been developed and screened for anti-inflammatory properties. Presented herein are three classes of prodrugs which dually target inflammation and cholinergic dysfunction. Compounds 1–28 contain common NSAIDs linked either to choline bioisosteres or to structural analogs of acetylcholinesterase (AChE) inhibitors. These agents have shown utility as anti-vesicants and anti-inflammatory agents when screened in a mouse ear vesicant model (MEVM) against both 2-chloroethyl ethyl sulfide (CEES), a blistering agent, and 12-O-tetradecanoylphorbol-13-acetate (TPA), a common topical irritant. Many of the prodrugs have activity against CEES, with 5, 18, 22 and 27 reducing inflammation by more than 75 % compared to a control. Compounds 12, 13, 15 and 22 show comparable activity against TPA. Promising activity in the MEVM is related to half-lives of NSAID-release in plasma, moderate to high lipophilicity, and some degree of inhibition of AChE, a potential contributor to sulfur mustard-mediated tissue damage.

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Section: Methodsmentioning

confidence: 97%

Investigation of anticholinergic and non‐steroidal anti‐inflammatory prodrugs which reduce chemically induced skin inflammation

Young

Fabio

Huang

et al. 2011

J of Applied Toxicology

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“…The cellinactive but animal toxic pancuronium is a non-depolarizing muscle relaxant inhibiting the nicotinic acetylcholine receptor. Neostigmine [45], pyridostigmine [46] and physostigmine are reversible inhibitors of cholinesterase; physostigmine can penetrate the blood-brain barrier. The examples in Fig.…”

Section: Cell Viability and Animal Toxicitymentioning

confidence: 99%

Utilizing high throughput screening data for predictive toxicology models: protocols and application to MLSCN assays

Guha

Schürer

2008

J Comput Aided Mol Des

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Computational toxicology is emerging as an encouraging alternative to experimental testing. The Molecular Libraries Screening Center Network (MLSCN) as part of the NIH Molecular Libraries Roadmap has recently started generating large and diverse screening datasets, which are publicly available in PubChem. In this report, we investigate various aspects of developing computational models to predict cell toxicity based on cell proliferation screening data generated in the MLSCN. By capturing feature-based information in those datasets, such predictive models would be useful in evaluating cell-based screening results in general (for example from reporter assays) and could be used as an aid to identify and eliminate potentially undesired compounds. Specifically we present the results of random forest ensemble models developed using different cell proliferation datasets and highlight protocols to take into account their extremely imbalanced nature. Depending on the nature of the datasets and the descriptors employed we were able to achieve percentage correct classification rates between 70% and 85% on the prediction set, though the accuracy rate dropped significantly when the models were applied to in vivo data. In this context we also compare the MLSCN cell proliferation results with animal acute toxicity data to investigate to what extent animal toxicity can be correlated and potentially predicted by proliferation results. Finally, we present a visualization technique that allows one to compare a new dataset to the training set of the models to decide whether the new dataset may be reliably predicted.

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“…The third aryl oxide group of the phosphite was derived from 4-imidazol-1-yl-phenol 7 and from either 3-or 4-(N,N-dimethylaminomethyl)-phenol (8 or 9), which were prepared from 3-or 4-hydroxybenzaldehyde by a reductive amination with dimethylamine and sodium triacetoxyborohydride in THF [26] (Scheme 7). Several aminoaryl phosphites were prepared by combination of these chlorophosphites and aminophenols and were obtained in modest to good yields (Scheme 8).…”

Section: Quaternization Of An Aminoaryl Phosphitementioning

confidence: 99%

“…Aminophenols. [26] Catalytic During this work, we were able to synthesize several cationic phosphites bearing a single cationic group with good to excellent purity. On the other hand, attempts at the synthesis of tri-cationic ligands led to only one ligand of moderate purity.…”

Section: Quaternization Of An Aminoaryl Phosphitementioning

confidence: 99%

Design of Ionic Phosphites for Catalytic Hydrocyanation Reaction of 3‐Pentenenitrile in Ionic Liquids^†

et al. 2005

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Abstract:The synthesis and characterization of a novel class of ionic phosphites bearing either a single cationic group obtained by quaternization of aminophosphites or three cationic groups prepared by reaction of phosphorus trichloride with imidazolium phenols are reported. The catalytic hydrocyanation reaction of 3-pentenenitrile (3PN) into adiponitrile has been performed in the presence of Ni(0) with ionic phosphite ligands, and a Lewis acid in biphasic ionic liquid/organic solvent system. The screening of several original cationic phosphites was performed and the experimental conditions were optimized for the tricationic phosphite tris-4-[(2,3-dimethylimidazol-1-yl) methyl]phenyl phosphite tris[bis(trifluoromethylsulfonyl)amide]. It is possible to obtain performance similar to molecular systems and the catalyst and the Lewis acid were immobilized in the ionic phase.

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Oxyaniliniums as acetylcholinesterase inhibitors for the reversal of neuromuscular block

Cited by 18 publications

References 6 publications

Investigation of anticholinergic and non‐steroidal anti‐inflammatory prodrugs which reduce chemically induced skin inflammation

Investigation of anticholinergic and non‐steroidal anti‐inflammatory prodrugs which reduce chemically induced skin inflammation

Utilizing high throughput screening data for predictive toxicology models: protocols and application to MLSCN assays

Design of Ionic Phosphites for Catalytic Hydrocyanation Reaction of 3‐Pentenenitrile in Ionic Liquids^†

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Oxyaniliniums as acetylcholinesterase inhibitors for the reversal of neuromuscular block

Cited by 18 publications

References 6 publications

Investigation of anticholinergic and non‐steroidal anti‐inflammatory prodrugs which reduce chemically induced skin inflammation

Investigation of anticholinergic and non‐steroidal anti‐inflammatory prodrugs which reduce chemically induced skin inflammation

Utilizing high throughput screening data for predictive toxicology models: protocols and application to MLSCN assays

Design of Ionic Phosphites for Catalytic Hydrocyanation Reaction of 3‐Pentenenitrile in Ionic Liquids†

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Design of Ionic Phosphites for Catalytic Hydrocyanation Reaction of 3‐Pentenenitrile in Ionic Liquids^†