Paraoxon anticholinesterase activity

Figure 5.5 The relationship between hydrolyzability and anticholinesterase activity for seven substituted diethyl phenyl phosphates, a, tetraethyl pyrophosphate b, paraoxon c, ortho analogue to paraoxon d, meta analogue to paraoxon e, o-chlo-rophenyl diethylphosphate f, p-chlorophenyl diethylphosphate g, phenyl phosphate. (Data from Aldridge and Davidson, 1952a, 1952b.)...

The discovery of prontosil was fortuitous and was not based on rationale design. There are a large number of pesticides which fall in the same category as prontosil, i.e., they are active by virtue of their susceptibility to metabolic or chemical modification to active intermediates. The classical example of an insecticide of this type is parathion, a phosphorothionate ester which in animals or plants is oxidatively desulfurated to the potent anticholinesterase paraoxon O). The insecticidal activity of parathion was known for several years before the purified material was shown to be a poor anticholinesterase and that metabolic activation to paraoxon was necessary for intoxication. 

It Is well known that phosphorothlonate insecticides such as parathlon (, 0-diethyl p-nitrophenyl phosphorothloate) and malathion [0, -dimethyl -(l,2 -dlcarbethoxy)ethyl phosphoro-dithioate] are Intrinsically poor inhibitors of acetylcholinesterase and in vivo activation to the respective anticholinesterases paraoxon and malaoxon is required before animals exposed to the phosphorothionates are intoxicated. Since metabolic activation is essential to the biological activity of these thiono sulfur-containing organophosphorus insecticides, compounds of this type may be considered as propesticides or, more specifically, prolnsectlcldes. 

The mechanism of toxicity for parathion is similar to that of chlorpyrifos. Following activation to the potent anticholinesterase paraoxon, acetylcholinesterase is inhibited within synapses and acetylcholine levels accumulate. This leads to overstimulation of cholinergic receptors of neurons, muscle cells, and end-organs culminating in cholinergic toxicity. 

---