Organophosphorus compounds (OP) pose a major threat to both military and civilian populations, causing up to 3 million poisonings worldwide every year. Some examples of these compounds are various pesticides and chemical warfare nerve agents of G and V class that can covalently bind to the catalytic Ser200 of human acetylcholinesterase and irreversibly inhibit enzyme’s activity. This leads to increased synaptic acetylcholine levels, a cholinergic crisis, and, ultimately, death. Only shortly after exposure to OPs can the inhibited enzyme be reactivated using oxime reactivators – strong nucleophiles that are able to cleave P-O bonds.
In this master thesis, we synthesised different oxime derivatives to selectively reactivate the OP-inhibited human butyrylcholinesterase (hBChE). Compounds 3 and 5 had moderate affinity for hBChE, and compound 5 was able to reactivate hBChE that had previously been inhibited by sarin and VX. Compound 18, a non-oxime hydroxypyridine derivative, also exhibited micromolar affinity for hBChE and is more likely to permeate the blood-brain barrier to reactivate cholinesterases in the central nervous system.
Pseudo-irreversible cholinesterase inhibitors with a carbamate scaffold are, among other things, prophylactically used in case of OP-exposure and for the treatment of Alzheimer's disease. We have prepared a focused library of carbamoyl fluorides, which feature fluoride as the leaving group instead of the usual phenols. We have synthesized them using a novel procedure via N-carbamoylimidazoles. These carbamoyl fluorides were mostly non-selective inhibitors of both cholinesterases.
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