1. Academic Validation
  2. Discovery of (E)-2-(hydroxyimino)-N-(2 ((4methylpentyl)amino)ethyl)acetamide (KR-27425) as a non-pyridinium oxime reactivator of paraoxon-inhibited acetylcholinesterase

Discovery of (E)-2-(hydroxyimino)-N-(2 ((4methylpentyl)amino)ethyl)acetamide (KR-27425) as a non-pyridinium oxime reactivator of paraoxon-inhibited acetylcholinesterase

  • Bioorg Med Chem Lett. 2023 Oct 12:96:129504. doi: 10.1016/j.bmcl.2023.129504.
Avinash G Vishakantegowda 1 Berehe Solomon Girmay 1 Jin Soo Shin 2 Joo-Youn Lee 2 Sunjoo Ahn 2 Young-Sik Jung 3
Affiliations

Affiliations

  • 1 Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, Republic of Korea.
  • 2 Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
  • 3 Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, Republic of Korea. Electronic address: ysjung@krict.re.kr.
Abstract

This study aimed to explore non-pyridinium oxime acetylcholinesterase (AChE) reactivators that could hold the potential to overcome the limitations of the currently available compounds used in the clinic to treat the neurologic manifestations induced by intoxication with organophosphorus agents. Fifteen compounds with various non-pyridinium oxime moieties were evaluated for AChE activity at different concentrations, including aldoximes, ketoximes, and α-ketoaldoximes. The therapeutic potential of the oxime compounds was evaluated by assessing their ability to reactivate AChE inhibited by paraoxon. Among the tested compounds, α-Ketoaldoxime derivative 13 showed the highest reactivation (%) reaching 67 % and 60 % AChE reactivation when evaluated against OP-inhibited electric eel AChE at concentrations of 1,000 and 100 μM, respectively. Compound 13 showed a comparable reactivation ability of AChE (60 %) compared to that of pralidoxime (56 %) at concentrations of 100 μM. Molecular docking simulation of the most active compounds 12 and 13 was conducted to predict the binding mode of the reactivation of electric eel AChE. As a result, a non-pyridinium oxime moiety 13, is a potential reactivator of OP-inhibited AChE and is taken as a lead compound for the development of novel AChE reactivators with enhanced capacity to freely cross the blood-brain barrier.

Keywords

Acetylcholinesterase; Organophosphorus agents; Oxime; Reactivator.

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