engleski

Natural deep eutectic solvents improve the solubility of acetylcholinesterase reactivator RS194B

Natural deep eutectic solvents (NADES) were studied as alternative solvents for the preparation of oxime RS194B, which is considered as a potent antidote for organophosphate (OP) poisoning. OPs are irreversible inhibitors of the essential enzyme acetylcholinesterase (AChE) and standard oximes used in therapy are insufficiently effective in the central nervous system. Nowadays, the focus is on the centrally active reactivators of phosphylated AChE such as oxime RS194B. The shortcoming of this oxime is its low solubility in water, and the aim of this study was the enhancement of the compound's solubility by preparing oxime formulations in NADES. The solubility of RS194B in various NADES was predicted by the COSMOtherm program and experimentally determined using high efficient liquid chromatography. The best oxime solubility was achieved with NADES citric acid:glucose (1:1) solvent with 30% (w/w) of water. Over a one-month period, there was no difference in the stability of oxime formulations in NADES and a reference solvent. Initial tests on the potential effects on enzyme activity showed that the selected NADES inhibits AChE, and its level should be kept below 0.2% in order for the enzyme to keep above 90% activity. Reactivation kinetic parameters of sarin- and VX-inhibited AChE were determined for both NADES and the reference solvent formulations of the oxime. Results showed an improvement in the AChE reactivation, as a consequence of the higher affinity of phosphylated AChE for the RS194B formulation in NADES. Although further optimizations are needed, this study is the first to show the NADES potential in formulating antidotes for nerve agent poisoning.

Antidote ; Cholinesterase ; COSMOtherm ; Oxime ; Natural deep eutectic solvents ; Solubility

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