Pralidoxime—an organophosphate antidote

Pralidoxime (Fig. 11.60) represents one of the best examples of rational drug design. It is an antidote to organophosphate poisoning and was designed as such. 

The problem faced in designing an antidote to organophosphate poisoning is to find a drug which will displace the organophosphate molecule from serine. This requires hydrolysis of the phosphate-serine bond, but this is a strong bond and not easily broken. Therefore, a stronger nucleophile than water is required. 

The literature revealed that phosphates can be hydrolysed with hydroxylamine (Fig. 11.61). This proved too toxic a compound to be used on humans, so the next 

Pralidoxime was the result. The positive charge is provided by a methylated pyridine ring and the nucleophilic side-group is attached to the ortho position, since it was calculated that this would place the nucleophilic hydroxyl group in exactly the correct position to react with the phosphate ester. The results were spectacular, with pralidoxime showing a potency as an antidote one million times greater than hydroxylamine. 

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