Oxime K203: a drug candidate for the treatment of tabun intoxication

Górecki, Lukáš; Soukup, Ondřej; Kučera, Tomáš; Maliňák, Dávid; Jun, Daniel; Kuča, Kamil; Musílek, Kamil; Korábečný, Jan

doi:10.1007/s00204-018-2377-7

Cited by 20 publications

(9 citation statements)

References 119 publications

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“…Nonetheless, similar spatial arrangement of aldoxime reactivators can be found in various docking studies and even in X-ray models of OP-inhibited AChE, co-crystalised with aldoximes (e.g. HI-6 in model pdb id: 5fpq) 25,26 . Despite the fact that molecular mechanics cannot in principle predict the necessary orientation of the aldoxime group towards the phosphorus atom because this follows only from quantum chemistry calculations, such initial unfavourable geometric arrangements suggest that reactivation requires certain degree of conformational flexibility of the moiety bearing the aldoxime function to enable reactivation.…”

Section: Molecular Docking Studiessupporting

confidence: 58%

Synthesis,in vitroscreening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

Maliňák

Doležal

Hepnarová

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators.

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Section: Molecular Docking Studiessupporting

confidence: 58%

Synthesis,in vitroscreening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

Maliňák

Doležal

Hepnarová

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…However, in vitro tests with rat brain AChE revealed only a moderate reactivation of tabun-, sarin- and VX-inhibited AChE using an extraordinary high K203 concentration (1 mM) but virtually no activity against cyclosarin and Russian VX. In later studies, K203 was proposed as a superior reactivator of tabun-inhibited AChE and in fact it turned out that K203 was a better reactivator compared to obidoxime but still too weak with a second order reactivation rate constant of 0.92 mM −1 min −1 (Kuca et al 2018 ; Gorecki et al 2019 ; Winter et al 2016 ).…”

Section: Novel Reactivatorsmentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.

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“…Their analogues with 4-positioned oxime and pyridinium-4-carboxamide moiety (e.g. K027, K048, K203, and K868) were described to have similar effectiveness for certain OP-inhibited AChE and valuable carboxamide binding in the AChE peripheral site 16,25 . However again, their reactivation of OP-inhibited BChE was rather limited with exception of K868 17 .…”

Section: Molecular Design and Synthesismentioning

confidence: 99%

Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates

Lee

Andrýs

Jończyk

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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The pyridinium-2-carbaldoximes with quinolinium carboxamide moiety were designed and synthesised as cholinesterase reactivators. The prepared compounds showed intermediate-to-high inhibition of both cholinesterases when compared to standard oximes. Their reactivation ability was evaluated in vitro on human recombinant acetylcholinesterase (hrAChE) and human recombinant butyrylcholinesterase (hrBChE) inhibited by nerve agent surrogates (NIMP, NEMP, and NEDPA) or paraoxon. In the reactivation screening, one compound was able to reactivate hrAChE inhibited by all used organophosphates and two novel compounds were able to reactivate NIMP/NEMP-hrBChE. The reactivation kinetics revealed compound 11 that proved to be excellent reactivator of paraoxon-hrAChE better to obidoxime and showed increased reactivation of NIMP/NEMP-hrBChE, although worse to obidoxime. The molecular interactions of studied reactivators were further identified by in silico calculations. Molecular modelling results revealed the importance of creation of the pre-reactivation complex that could lead to better reactivation of both cholinesterases together with reducing particular interactions for lower intrinsic inhibition by the oxime.

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Oxime K203: a drug candidate for the treatment of tabun intoxication

Cited by 20 publications

References 119 publications

Synthesis,in vitroscreening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

Synthesis,in vitroscreening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators

Organophosphorus compounds and oximes: a critical review

Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates

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