Bis-pyridiumaldoxime reactivators connected with CH2O(CH2) OCH2 linkers between pyridinium rings and their reactivity against VX

Oh, Kyung-Ae; Yang, Garp Yeol; Jun, Daniel; Kuča, Kamil; Jung, Young‐Sik

doi:10.1016/j.bmcl.2006.06.063

Cited by 26 publications

(19 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The oxime 12 was more potent than 2-PAM, and was very potent for HF-AChE inhibited and RBC-AChE inhibited by paraoxon. In reactivation evaluation against VX, the oxime 12 was the most potent VX-inhibited AChE reactivator [14]. The oxime 12 is able to reactivate VX-inhibited AChE at concentrations 10 -3 M (44%) and 10 -5 M (15%), respectively.…”

Section: Reactivation Potencymentioning

confidence: 99%

“…We were especially interested in incorporation of an oxygen atom in the spacer connecting the two pyridinium rings, because oxime reactivators with linkers having oxygen atom and methylene such as obidoxime and HI-6 showed strong reactivation activity. These speculations prompted us to design new oximes in which a longer ether linker was introduced to connect the two pyridine rings, CH 2 O(CH 2 ) n OCH 2 linkers between the two quaternary nitrogens [14] (Fig. 7).…”

Section: Bis-pyridinium Oximes With (Ch 2 )O(ch 2 ) N O(ch 2 ) Linkersmentioning

confidence: 99%

“…at 45 o C for 20 h. Similarly the other oximes (14,15) were prepared by the reaction of 5 or 7 with 17 in DMF at r.t. for 24 h.…”

Section: Chemistrymentioning

confidence: 99%

See 2 more Smart Citations

Current Study on the Development of Bis-pyridinium Oxime Reactivators for the Antidotal Treatment of Poisoning by Toxic Organophosphorus Agents

Kuca¹

2011

COC

Self Cite

View full text Add to dashboard Cite

A number of oxime reactivators have been synthesized and studied for the antidotal treatment of poisoning by toxic organophosphorus agents, and several oximes are currently available to reactivate the organophosphorus agents-induced acetylcholinesterase inhibition. However, there is no oxime with broad spectrum suitable for the antidotal treatment of poisoning with various organoposphorus warfare agents as well as insecticides. In addition, current available oximes have very limited brain-blood barrier (BBB) penetration, even though hydrophobic toxic organophosphorus agents can easily penetrate BBB. Therefore, the development of BBB permeable oxime reactivators is one of great challenges in these days. In this review, we summarize advances in the synthesis and reactivation evaluation of oximes that have been studied in our research group. Various approaches have been employed to design these analogs; for example, bispyridinium oximes with (CH2)2O(CH2)2 linkers, (CH2)O(CH2)nO(CH2) linkers and (CH2)n linkers as well as fluorinated bis-pyridinium oximes.

show abstract

Section: Reactivation Potencymentioning

confidence: 99%

Section: Bis-pyridinium Oximes With (Ch 2 )O(ch 2 ) N O(ch 2 ) Linkersmentioning

confidence: 99%

See 1 more Smart Citation

Current Study on the Development of Bis-pyridinium Oxime Reactivators for the Antidotal Treatment of Poisoning by Toxic Organophosphorus Agents

Kuca¹

2011

COC

Self Cite

View full text Add to dashboard Cite

show abstract

“…The promising new oxime HI-6 (1) seemed to be a solution, but its potency to reactivate tabun or pesticide poisoning is poor [12][13][14][15][16]. Due to this, new compounds are being developed and tested for their reactivation potency [17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Targeted Synthesis of 1-(4-Hydroxyiminomethylpyridinium)-3-pyridiniumpropane Dibromide – A New Nerve Agent Reactivator

Kuča¹,

Musílek²,

Paar³

et al. 2007

Molecules

Self Cite

View full text Add to dashboard Cite

Preparation of 1-(4-hydroxy-iminomethylpyridinium)-3-pyridiniumpropane dibromide is described. This compound represents a new acetylcholinesterase (AChE) reactivator, which has no substituents on the second pyridinium ring as found in other commonly used AChE reactivators. The reactivation ability of this reactivator was tested on tabun-and cyclosarin-inhibited AChE. According to the results obtained, the new compound (without substitution and with decreased molecule size) showed increased reactivation potency in case of cyclosarin inhibited AChE. A potent oxime for treatment of tabun and cyclosarin-caused intoxications was thus obtained via slight modification of the reactivator structure (compared to trimedoxime and K027).

show abstract

“…So, although an increase in AChE activity of 5-10 per cent allows for survival in cases of organophosphorus intoxication 45,46 , neutral oxime 5 could not be designated as a good reactivator. At a concentration of 200 µM, neutral oxime 1 presented reactivation potency similar to that of neutral oxime 2 and was unable to reactivate AChE at a concentration of 1000 µM.…”

mentioning

confidence: 99%

In vitro evaluation of neutral oximes as reactivators of parathion-inhibited electric eel acetylcholinesterase

et al. 2017

View full text Add to dashboard Cite

Organophosphorus (OP) compounds are irreversible inhibitors of acetylcholinesterase (AChE) commonly used as pesticides and, unfortunately, as nerve agents in terrorist attacks. These compounds are highly soluble easily crossing the blood-brain barrier (BBB). Clinically, oximes such as pralidoxime and obidoxime are used for the reactivation of AChE. These oximes are not effective to reactivate AChE inhibited by different OPs besides the fact that they are permanently charged and do not readily cross the BBB. This work evaluated the ability of ten neutral oximes to reactivate parathion-inhibited eel AChE. Because oximes can bind to AChE as reversible inhibitors, this property was also evaluated, with pralidoxime (2-PAM) used as a reference compound. Unlike 2-PAM, which inhibited AChE in a concentration-dependent way, neutral oximes did not follow the linear order of AChE inhibition. Neutral ligands can present affinity for the periferic anionic site (PAS) site. Neutral oximes 1 and 2 (200 µM) reactivated parathion-inhibited eel AChE by 9 per cent and 11 per cent, respectively; but neither of them surpassed the reactivation efficacy of 2-PAM (25 per cent). Neutral oximes 1 and 2 reactivated AChE at a safe concentration for humans. Both neutral oximes 1 and 2 are good non-quaternary moieties for the synthesis of conjugates with enhanced reactivation potency and BBB penetration.Keywords: Acetylcholinesterase; Eel AChE; Reactivator; Oxime; Pralidoxime; Parathion RESEARCH PAPERDefence Life Science Journal, Vol. 2, No. 3, July 2017, pp. 363-369, DOI : 10.14429 LIMA, et al.: DEf. LIfE SCI. J., VOL. 2, NO. 3, JULy 2017, DOI : 10.14429/dlsj.2.10730 or allosteric) 14 . Although approved as antidotes, these oximes are not sufficiently effective to reactivate AChE inhibited by the different OPs 15,16 . The mono-quaternary oxime 2-PAM is very efficient in reactivating AChE inhibited with sarin or VX 17 but is not effective against tabun or soman 18 . Obidoxime is the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun, but was inferior to oxime HI-6 against soman, sarin, cyclosarin and VX 19. A significant drawback to these oximes is they are permanently charged and do not readily cross the blood brain barrier (BBB) 20 . As a result, they show only limited activity in the CNS, which is a major target of OPs. Thus, effective reactivators as antidotes are increasingly needed against a broader spectrum of nerve agents 21 . Introducing non-quaternary organic compounds has been a novel method of efficiently penetrate the BBB for reactivation of brain AChE 22. Non-charged oximes have previously been developed with improved BBB penetration [23][24][25][26][27][28][29] and sufficient reactivation of AChE inhibited by nerve agents and insecticides 24,30 . Even with improved BBB penetration and reactivation of AChE, the specific oxime structures with superior reactivating potency to those in use remain unknown.The work proposed here evaluated the ability of...

show abstract

Bis-pyridiumaldoxime reactivators connected with CH2O(CH2) OCH2 linkers between pyridinium rings and their reactivity against VX

Cited by 26 publications

References 18 publications

Current Study on the Development of Bis-pyridinium Oxime Reactivators for the Antidotal Treatment of Poisoning by Toxic Organophosphorus Agents

Current Study on the Development of Bis-pyridinium Oxime Reactivators for the Antidotal Treatment of Poisoning by Toxic Organophosphorus Agents

Targeted Synthesis of 1-(4-Hydroxyiminomethylpyridinium)-3-pyridiniumpropane Dibromide – A New Nerve Agent Reactivator

In vitro evaluation of neutral oximes as reactivators of parathion-inhibited electric eel acetylcholinesterase

Contact Info

Product

Resources

About