engleski

Cytotoxicity of oxime antidotes driven by changes in their structure

Compounds known as oximes are investigated today as antidotes in highly toxic organophosphorus pesticide and nerve warfare agent (OPs) poisonings. Their major advantage is the ability to act fast by reactivating the essential enzyme acetylcholinesterase (AChE, EC 3.1.1.7), the main OP target in neural synapses. However, in the last 70 years, only two oximes have been introduced to medical practice, unfortunately, both with a narrow scope of action. The search for more efficient oxime antidotes is still ongoing and diverse chemical structures are being tested with groups added to the core structure to enhance properties such as lipophilicity and blood brain barrier penetration. The major issue for oximes in the early stages of drug development is the high cut-off rate due to observed side- effects and a possible negative influence on organs. For that reason, we wanted to investigate what drives this toxicity and whether it could be related to oxime’s specific structural motives. We tested the influence of four diverse sets of potential oxime antidotes on the viability of several different cell types representing nerves, muscles, liver and kidneys. The toxic effect was monitored for each compound in a time- and dose-dependent manner, and the type of cell death was assessed. As the results indicated, the observed negative effects were triggered by the presence of specific moieties within the oxime structure or by the presence of specific structural feature combinations. The most toxic oximes had the 6, 7-dimethoxy-isoquinoline group or chlorine atoms present in their structure. With respect to this finding, studies designing these drugs will have to consider other options for oxime structure modifications to aid the challenging development of a more effective treatment for OP poisoning. Furthermore, we designed a pharmacophore model for the tested set of oximes and ran it through the database carrying information about associated cell targets and mechanisms of action responsible for the observed biological phenotype. The provided information will subsequently be used to narrow down the choice of possible cell targets of the tested oximes as well as the experimental method used to ascertain the assumed interaction. Acknowledgment: This work was supported in part by the Croatian Science Foundation under project UIP-2017-05-7260 and by the Slovenian Research Agency research programme P3-0043.

Oximes ; cytotoxicity ; nerve agents ; cell culture ; pharmacophore

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