Synthesis and Evaluation of Halogenated Pralidoximes in Reactivation of Organophosphate-Inhibited Cholinesterases.

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-12-02 eCollection Date: 2024-12-12 DOI:10.1021/acsmedchemlett.4c00464

Karolina Knittelova, Eliska Prchalova, Adela Fuchsova, Rudolf Andrys, Zuzana Kohoutova, Sara Rademacherova, Lukas Prchal, Kamil Musilek, David Malinak

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Abstract

Organophosphorus compounds are highly toxic irreversible inhibitors of cholinesterases, causing the disruption of cholinergic functions. Treatment of poisoning includes causal antidotes (oximes) used as reactivators of inhibited cholinesterases, such as pralidoxime. In this work, new halogenated oxime reactivators derived from pralidoxime were developed. The oximes were designed with a halogen substituent that lowers the pK _a and enhances oximate formation. Their synthesis, stability, physicochemical properties, inhibition of native cholinesterases, and in vitro reactivation of organophosphate-inhibited cholinesterases were investigated. A series of C4 and C6 halogenated oximes showed instability and their degradation products were identified, while C3 and C5 oximes exhibited sufficient stability for the evaluation. C3 oximes displayed overall low inhibition of cholinesterases and high reactivation ability of organophosphate-inhibited cholinesterases compared to pralidoxime, indicating the significant impact of halogen substitution on reactivation ability.

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卤代哌啶多肟的合成及其对有机磷抑制胆碱酯酶的活性评价。

有机磷化合物是高毒性的不可逆的胆碱酯酶抑制剂，引起胆碱能功能的破坏。中毒的治疗包括使用因果解毒剂（肟）作为抑制胆碱酯酶的再激活剂，如普拉多肟。本研究开发了由普拉西肟衍生的新型卤化肟活化剂。设计了一个卤素取代基，降低了pK a，促进了肟的形成。研究了它们的合成、稳定性、理化性质、对天然胆碱酯酶的抑制作用以及有机磷酸酯抑制胆碱酯酶的体外再激活。一系列C4和C6卤化肟表现出不稳定性，并确定了其降解产物，而C3和C5肟表现出足够的稳定性，可用于评价。与普拉度肟相比，C3肟对胆碱酯酶的总体抑制作用较低，对有机磷抑制的胆碱酯酶的再激活能力较高，表明卤素替代对胆碱酯酶的再激活能力有显著影响。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.