Halogenated monopyridinium oximes are less effective in reactivation of phosphylated cholinesterases than bisquaternary oximes

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F24%3A50021852" target="_blank" >RIV/62690094:18470/24:50021852 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00179906:_____/24:10489309

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0045206824008095?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0045206824008095?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bioorg.2024.107904" target="_blank" >10.1016/j.bioorg.2024.107904</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Halogenated monopyridinium oximes are less effective in reactivation of phosphylated cholinesterases than bisquaternary oximes

Popis výsledku v původním jazyce

Mono-quaternary pyridinium oximes derived from K-oximes K027, K048 and K203 were designed, synthesized and evaluated for the reactivation of organophosphate-inhibited cholinesterases. The incorporation of the halogen atoms to the structure decreased the pKa value of the oxime group resulting in an increased formation of oximate necessary for reactivation. The stability and pKa values were found to be similar to analogous bis-quaternary compounds. Some mono-quaternary oximes resulted as relatively strong inhibitors of human acetylcholinesterase. Nevertheless, the reactivation ability of mono-quaternary oximes for organophosphate-inhibited cholinesterases was lower compared to their bis-quaternary analogues. These results were further confirmed by the determination of reactivation kinetics, when in some cases novel compounds showed improvement reactivation compared to the tested standards, but no improvement to bis-quaternary K-oximes. A computational study investigated reactivation process for K027, and its two analogues for VX-inhibited AChE. This study revealed slight differences between reactivation of mono-quaternary and bis-quaternary oximes. Abbreviations: 2-PAM, pralidoxime; AChE, acetylcholinesterase; ACN, acetonitrile; ATCI, acetylcholine iodide; BChE, butyrylcholinesterase; BTCI, butyrylcholine iodide; Bu3SnSnBu3, bis(tributyltin) Et2O, diethyl ether; ChEs, cholinesterases; CNS, central nervous system; DAD, diode array detector; DIBAL-H, diisobutylaluminium hydride; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; DTNB, 5,5́-dithiobis-2-nitrobenzoic acid; Et3N, triethylamine; EtOAc, ethyl acetate; EWG, electron withdrawing group; HI-6, asoxime; hrAChE, human recombinant acetylcholinesterase; hrBChE, human recombinant butyrylcholinesterase; hrChEs, human recombinant cholinesterases; HPLC, high-performance liquid chromatography; HRMS, high-resolution mass spectrometry; KD, dissociation constant; kr, first-order reactivation rate constant; kr2, second-order reactivation rate constant; LüH-6, obidoxime; MeOH, methanol; MM, molecular mechanics; MMC-4, methoxime; m.p., melting point; NCIs, non-covalent interactions; NEDPA, 4-nitrophenyl ethyl dimethylphosphoramidate; NEMP, 4-nitrophenyl ethyl methylphosphonate; NIMP, isopropyl methylphosphonate; NMR, nuclear magnetic resonance spectroscopy; OPs, organophosphates; PBS, phosphate-buffered saline; Pd(dppf)Cl2.CH2Cl2, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) in complex with dichloromethane; pKa, negative decimal logarithm of the dissociation constant; POX, paraoxon; PPh3, triphenylphosphine; QM, quantum mechanics; rt, room temperature; SN2, bimolecular nucleophilic substitution; SNAc, nucleophilic acyl substitution; THF, tetrahydrofuran; TMC-4, trimedoxime; TNB, 5-thio-2-nitrobenzoic acid; UHPLC, ultra high-performance liquid chromatography; UV, ultraviolet; UV–VIS, ultraviolet–visible. © 2024 Elsevier Inc.

Název v anglickém jazyce

Halogenated monopyridinium oximes are less effective in reactivation of phosphylated cholinesterases than bisquaternary oximes

Popis výsledku anglicky

Mono-quaternary pyridinium oximes derived from K-oximes K027, K048 and K203 were designed, synthesized and evaluated for the reactivation of organophosphate-inhibited cholinesterases. The incorporation of the halogen atoms to the structure decreased the pKa value of the oxime group resulting in an increased formation of oximate necessary for reactivation. The stability and pKa values were found to be similar to analogous bis-quaternary compounds. Some mono-quaternary oximes resulted as relatively strong inhibitors of human acetylcholinesterase. Nevertheless, the reactivation ability of mono-quaternary oximes for organophosphate-inhibited cholinesterases was lower compared to their bis-quaternary analogues. These results were further confirmed by the determination of reactivation kinetics, when in some cases novel compounds showed improvement reactivation compared to the tested standards, but no improvement to bis-quaternary K-oximes. A computational study investigated reactivation process for K027, and its two analogues for VX-inhibited AChE. This study revealed slight differences between reactivation of mono-quaternary and bis-quaternary oximes. Abbreviations: 2-PAM, pralidoxime; AChE, acetylcholinesterase; ACN, acetonitrile; ATCI, acetylcholine iodide; BChE, butyrylcholinesterase; BTCI, butyrylcholine iodide; Bu3SnSnBu3, bis(tributyltin) Et2O, diethyl ether; ChEs, cholinesterases; CNS, central nervous system; DAD, diode array detector; DIBAL-H, diisobutylaluminium hydride; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; DTNB, 5,5́-dithiobis-2-nitrobenzoic acid; Et3N, triethylamine; EtOAc, ethyl acetate; EWG, electron withdrawing group; HI-6, asoxime; hrAChE, human recombinant acetylcholinesterase; hrBChE, human recombinant butyrylcholinesterase; hrChEs, human recombinant cholinesterases; HPLC, high-performance liquid chromatography; HRMS, high-resolution mass spectrometry; KD, dissociation constant; kr, first-order reactivation rate constant; kr2, second-order reactivation rate constant; LüH-6, obidoxime; MeOH, methanol; MM, molecular mechanics; MMC-4, methoxime; m.p., melting point; NCIs, non-covalent interactions; NEDPA, 4-nitrophenyl ethyl dimethylphosphoramidate; NEMP, 4-nitrophenyl ethyl methylphosphonate; NIMP, isopropyl methylphosphonate; NMR, nuclear magnetic resonance spectroscopy; OPs, organophosphates; PBS, phosphate-buffered saline; Pd(dppf)Cl2.CH2Cl2, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) in complex with dichloromethane; pKa, negative decimal logarithm of the dissociation constant; POX, paraoxon; PPh3, triphenylphosphine; QM, quantum mechanics; rt, room temperature; SN2, bimolecular nucleophilic substitution; SNAc, nucleophilic acyl substitution; THF, tetrahydrofuran; TMC-4, trimedoxime; TNB, 5-thio-2-nitrobenzoic acid; UHPLC, ultra high-performance liquid chromatography; UV, ultraviolet; UV–VIS, ultraviolet–visible. © 2024 Elsevier Inc.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30108 - Toxicology

Projekt

<a href="/cs/project/GA21-03000S" target="_blank" >GA21-03000S: Modifikované nukleofily pro reaktivaci cholinesteras inhibovaných organofosforovými sloučeninami</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Bioorganic Chemistry

ISSN

0045-2068

e-ISSN

1090-2120

Svazek periodika

153

Číslo periodika v rámci svazku

December

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

"Article Number: 107904"

Kód UT WoS článku

001368349800001

EID výsledku v databázi Scopus

2-s2.0-85207664332