Sustainable ionic liquids-based molecular platforms for designing acetylcholinesterase reactivators
Illia V Kapitanov1, Marcel Špulák2, Milan Pour2
1Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia Tee 15, 12618 Tallinn, Estonia.
Chemico-Biological Interactions
|October 6, 2023
Summary
Novel oxime-functionalized ionic liquids (ILs) were synthesized as acetylcholinesterase (AChE) reactivators. One compound demonstrated superior efficacy against VX-inhibited AChE compared to standard treatments, showing low toxicity.
Area of Science:
- Green chemistry
- Medicinal chemistry
- Biochemistry
Background:
- Organophosphate (OP) poisoning remains a significant threat, necessitating effective acetylcholinesterase (AChE) reactivators.
- Current reactivators have limitations, driving the search for novel therapeutic agents.
- Ionic liquids (ILs) offer tunable properties for drug development.
Purpose of the Study:
- To develop novel oxime-functionalized ILs as potential AChE reactivators.
- To evaluate the efficacy and safety profile of these synthesized compounds.
- To investigate structure-activity relationships for improved antidotal properties.
Main Methods:
- Green chemistry synthesis of amide/ester linked ILs with pyridinium aldoxime moiety.
- In vitro evaluation of AChE reactivation against sarin (GB), VX, and paraoxon (PON) inhibited enzymes.
- Cytotoxicity assays against bacterial, fungal, and eukaryotic cell lines (CHO-K1).
- Biodegradability and plasma stability assessments.
- Molecular docking studies.
Main Results:
- Synthesized novel oxime-functionalized ILs with varying linker types (amide/ester) and amino acid derivatives (l-alanine, l-phenylalanine).
- Compounds showed significant AChE reactivation, with compound 3d exhibiting remarkable activity against VX-inhibited AChE, surpassing 2-PAM and obidoxime.
- Most compounds displayed low toxicity across tested microbial and eukaryotic cell lines up to 2 mM.
- Introduction of the oxime moiety reduced biodegradability of the parent structures.
- Molecular docking provided insights into binding interactions.
Conclusions:
- Oxime-functionalized ILs represent a promising class of AChE reactivators with a favorable safety profile.
- Compound 3d shows potential as a next-generation antidote for OP poisoning, particularly against VX.
- Further structural modifications based on observed regularities are expected to enhance antidotal activity, stability, and biodegradability.
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