Neurotoxic organophosphates (OPs) pose a serious health threat to global populations. Despite the availability of numerous antidotes, current regimens to treat OP exposure are limited in their efficacy. Here we report our efforts towards this unmet need by applying an innovative design paradigm that has led to the identification of antidote-like, dual-acting molecules. It involves a focused library composed of three α-nucleophilic scaffold series, each designed to inactivate OP through nucleophilic catalysis by which acetylcholinesterase (AChE), the primary enzyme targeted by OPs, is protected. This paper discusses details on their structure, reactivity, and lead identification in two aspects. First, the chemical aspect of OP inactivation by α-nucleophiles is discussed using paraoxon (POX) as a model OP with regards to the reaction rate, catalytic mechanism, pH models and thermodynamics. Second, the benefits of OP inactivation are discussed in the biological aspect by determining their efficacy in a skin decontamination model in porcine skin <i>ex vivo, </i>and their activity to protect AChE from POX <i>in vitro</i>. In summary, this paper reports the rational design and mechanistic validation of novel α-nucleophilic compounds as a promising class of therapeutic agents for addressing OP exposure.

Reactivity and dual mechanism of action of α-nucleophile scaffolds for the protection of acetylcholinesterase

2019 Spring National Meeting

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