Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase

Kliachyna, Maria; Santoni, Gianluca; Nussbaum, Valentin; Renou, Julien; Sanson, B.; Colletier, J.P.; Arboléas, Mélanie; Loiodice, Mélanie; Weik, Martin H.; Jean, Ludovic; Renard, Pierre; Nachon, Florian; Baati, Rachid

doi:10.1016/j.ejmech.2014.03.044

Cited by 72 publications

(70 citation statements)

References 44 publications

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“…With such a low barrier, it appears that AChE reactivation by oximes is solely dependent on the protonation state in the active site rather than nucleophilicity of the oxime. Obviously, binding of the oxime is also important, but this has been largely addressed by experimental and docking studies …”

Section: Discussionmentioning

confidence: 99%

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

Driant

Nachon²,

Ollivier

et al. 2017

ChemBioChem

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Acetylcholinesterase (AChE) is an enzyme of the serine hydrolase superfamily and a mediator of the signal transmission at cholinergic synapses catalysing acetylcholine cleavage into an acetate and a choline. This enzyme is vulnerable to covalent inhibition by organophosphate compounds. The covalent inhibition of AChE does not revert spontaneously and in order to restore catalytic activity known reactivator compounds have limited action. Simulations of VX-inhibited AChE reactivation by pralidoxime, a classical reactivator, were performed by QM/MM. These simulations allowed for a broader view of the effect of protonation states of active site residues. These calculations provide evidence for the role of Glu202, which needs to be protonated for reactivation to occur. In situ deprotonation of 2-PAM was also explored in both protonation states of Glu202, showing that His447 is able to deprotonate 2-PAM with the assistance of Glu202. Since the active site of serine hydrolases is highly conserved, this work shades new insights on the interplay between the triad residues of the catalytic center and this glutamate newly identified as protonatable.

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Section: Discussionmentioning

confidence: 99%

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

Driant

Nachon²,

Ollivier

et al. 2017

ChemBioChem

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“…Since the pesticides involving the pyridine element have the general features of high efficiency, low toxicity, and good compatibility with the ecological environment, they meet the requirements of integrated pest management, and these chemicals have already received great interest from contemporary agricultural chemists . For example, Kliachyna et al thought that a series of chemicals involving the structural component of 3‐hydroxy‐2‐pyridine can act on acetylcholinesterase according to the in vitro biological investigation, and thus these compounds have the probability of becoming a class of nerve agent. Liu et al synthesised a number of new 1,2,4‐triazolo[4,3‐ a ]pyridine derivatives through a microwave irradiation technique, and bioassay revealed distinctly that such compounds have generally good antifungal activity, and the bioactivity of part agents (e.g.…”

Section: Introductionmentioning

confidence: 99%

Quantitative structure–activity relationship (QSAR) directed the discovery of 3‐(pyridin‐2‐yl)benzenesulfonamide derivatives as novel herbicidal agents

Xie

Peng

Ding

et al. 2017

Pest Management Science

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BACKGROUND: Agrochemicals have been crucial to the production of food, and the need for the development of novel agrochemicals continues unceasing owing to the loss of existing produces via the growth of resistance and the desire for products with more propitious environmental and toxicological patterns. RESULTS:The results of both CoMFA and CoMSIA models indicated that biological activity can effectively be improved through the structural optimisation and molecular design of these synthetic compounds from the aspects of steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. Data of postemergence herbicidal activity in the greenhouse explained that most new 3-(pyridin-2-yl)benzenesulfonamide derivatives (4c-4 t) could control highly effectively against barnyardgrass, foxtail, vetleaf, and youth and old age (herbicidal activity ≥90%); for example, compounds 4q-4 t exhibit excellent biological activity equivalent/superior to commercial saflufenacil/sulcotrione at the low concentration of 37.5 g a.i./ha, and in particular, the herbicidal activity of compound 4 t for four experimental plant species is found to be notably greater than saflufenacil (3.75 g a.i./ha). Meanwhile, compound 4 t also has good crop selectivity for weed control in maize. CONCLUSION:The novel compounds such as 4 t have remarkable biological activity after the structural optimisation utilising the constructed 3D-QSAR models, i.e. such QSAR models have great accuracy.

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“…N -substituted amidines, similar to well known simple amidoximes (Abele et al 2003), have already been used as antimicrobial (Hall et al 1998; Boykin et al 1996), insecticidal (Paul 1981), herbicidal or plant growth regulatory agents (Farge et al 1978, 1980) as well as DNA photo-cleavage agents (Karamtzioti et al 2015) reactivators of nerve agent and pesticide poisoning (Kliachyna et al 2014) and as regulator of blood pressure (Izawa et al 1993). The most important key issues for the preparation of such compounds are a complexing nature of the N -hydroxypyridine-2- or -4-carboximidamide, which can coordinate to the divalent metal ions mainly through their pyridine or amine and imine nitrogen atom forming five- or six-membered chelate rings (Salonen et al 2008; Salonen 2010; Konidaris et al 2011; Coropceanu et al 2014; Nandy et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of amphiphilic N-alkyloxypyridinecarboximidamide by liquid chromatography–tandem mass spectrometry

Wojciechowska

Wieszczycka

et al. 2016

Chem. Pap.

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LC–MS/MS method to determine hydrophobic N-alkyloxy substituted amidines: N-(2-ethylhexyloxy)pyridine-2-carboximidamide, N-(2-ethylhexyloxy)pyridine-3-carboximidamide, N-(2-ethylhexyloxy)pyridine-4-carboximidamide, N-decyloxy pyridine-2-carboximidamide, N-decyloxypyridine-3-carboximidamide and N-decyloxypyridine-4-carboximidamide was developed and validated in terms of linearity, precision and accuracy. The developed method was successfully applied to monitor and control the synthesis process. The experimental data points indicated that the straight chain alkyl bromide reacted most rapidly than branched alkyl bromide and the enhancement of the reaction efficiency strongly depended on reaction temperature.

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Design, synthesis and biological evaluation of novel tetrahydroacridine pyridine- aldoxime and -amidoxime hybrids as efficient uncharged reactivators of nerve agent-inhibited human acetylcholinesterase

Cited by 72 publications

References 44 publications

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

Quantitative structure–activity relationship (QSAR) directed the discovery of 3‐(pyridin‐2‐yl)benzenesulfonamide derivatives as novel herbicidal agents

Quantitative analysis of amphiphilic N-alkyloxypyridinecarboximidamide by liquid chromatography–tandem mass spectrometry

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