Pro: Oximes should be used routinely in organophosphate poisoning

Thiermann, Horst; Worek, Franz

doi:10.1111/bcp.15215

Cited by 11 publications

(3 citation statements)

References 68 publications

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“…Reference or standard oximes are usually specific to individual OP compounds and are not broad-spectrum [ 3 , 4 , 5 , 6 , 7 ]. In addition to the lack of universal access, another problem with reference oximes is their pharmacological properties, which are defined by their rapid dissociation in the body into ionized forms [ 8 , 9 , 10 ]. Hydrophilic oximes with a charged nitrogen atom hardly pass through the blood–brain barrier (BBB) to central synapses.…”

Section: Introductionmentioning

confidence: 99%

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

Mlakić,

Čadež,

Šinko

et al. 2024

Biomolecules

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New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents–sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

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Section: Introductionmentioning

confidence: 99%

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

Mlakić,

Čadež,

Šinko

et al. 2024

Biomolecules

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show abstract

“…Reference or standard oximes are usually specific to individual OP compounds and are not broad-spectrum [3][4][5][6][7]. In addition to the lack of 2 universal access, another problem with reference oximes is their pharmacological properties, which are defined by their rapid dissociation in the body into ionized form [8]. Hydrophilic oximes with a charged nitrogen atom hardly pass through the blood-brain barrier (BBB) to central synapses.…”

Section: Introductionmentioning

confidence: 99%

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

Mlakić,

Čadež,

Šinko

et al. 2024

Preprint

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New furan, thiophene and triazole oximes were synthesized through several-step reaction paths to investigate their potential for development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Acute OP poisoning is still a challenge in treating patients despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, are blocked by the OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to cholinergic crisis. Oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper we described the synthesis of 63 heterostilbene derivatives out of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents – sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in micromolar range, we identified several oximes as BChE or AChE selective inhibitors with a potential for drug development. Moreover, even oximes were poor reactivators of AChE, four heterocyclic derivatives reactivated the cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had comparable reactivation efficacy to the standard oxime HI-6. In silico analysis and molecular docking studies connected the kinetic data to the structural features of these oximes, and confirmed their productive interactions with the active site of the cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases like Alzheimer’s and Parkinson’s.

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“…Irwin Wilson found that an oxime restored acetylcholinesterase activity by chemically removing the inhibitor from serine at the active site (Wilson & Ginsburg, 1955). Oximes are now a standard antidote used for treatment of poisoning by nerve agents and organophosphorus pesticides (Thiermann & Worek, 2022).…”

Section: Introductionmentioning

confidence: 99%

Overview of Adductomics in Toxicology

Lockridge

2023

Current Protocols

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Adductomics is epidemiology at the molecular level. Untargeted adductomics compares levels of chemical adducts on albumin, hemoglobin, and DNA between healthy and exposed individuals. The goal is to determine a cause-and-effect relationship between chemical exposure and illness. Chemical exposures are not necessarily due to synthetic chemicals but are often due to oxidation products of naturally occurring lipids, for example, 4-hydroxynonenal and acrolein produced by lipid peroxidation of arachidonic and linoleic acids. The preferred method used in adductomics is ultra-high pressure liquid chromatography coupled to with nanoelectrospray tandem mass spectrometry. The mass of the adduct indicates its structure and identifies the chemical. The advantages of molecular epidemiology include information about the many toxicants to which a person is exposed over a period of weeks or months and the relative exposure levels. The disadvantage is the absence of information about the mechanism of toxicity. Untargeted adductomics examines albumin and hemoglobin adducts, which serve as biomarkers of exposure but do not identify the proteins and genes responsible for the toxicity. Targeted adductomics is used when the origin of the toxicity is known. This can be either an adducted protein, such as the butyrylcholinesterase protein modified by nerve agents, or a toxicant, such as acetaminophen. Untargeted adductomics methods have identified potential protein adduct biomarkers of breast cancer, colorectal cancer, childhood leukemia, and lung cancer. Adductomics is a new research area that offers structural insights into chemical exposures and a platform for the discovery of disease biomarkers.

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Pro: Oximes should be used routinely in organophosphate poisoning

Cited by 11 publications

References 68 publications

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

Overview of Adductomics in Toxicology

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