Oxime antidotes against anticholinesterase poisoning : a study of prodrugs, synthesis and biochemistry

Abstract

Acetylcholinesterase (AChE) is an enzyme crucial to normal nerve signaling because of its rapid hydrolysis of acetylcholine, a common neurotransmitter. Inhibition of this enzyme may cause bradycardia, hypotension and difficulty in breathing, and the outcome might be deadly. Nerve agents are a group of lipophilic and volatile organophosphorous AChE inhibitors. Because of their ability to penetrate unbroken skin and pass into the central nervous system (CNS), they are ideal for chemical warfare. A group of mono-and bispyridinium compounds called oximes are able to reactivate inhibited AChE, and there is great interest in synthesizing better and more effective oximes. To be able to reactivate inhibited AChE the pyridine nitrogen has to be positively charged, but due this positive charge the oximes have problems passing the blood- brain- barrier (BBB) and enter the CNS. As a consequence of this, nerve agent intoxication is difficult to treat. The solution to this problem may be to synthesize an oxime prodrug; in other words a compound that can freely pass the BBB (e. g has lipophilic properties) and enter the CNS, and once inside the CNS regain its active form. When a polar compound like an oxime has successfully entered the CNS, it is in reality trapped. Little progress has been made in regard to synthesizing an effective oxime prodrug since the pralidoxime prodrug was synthesized in 1975. New oximes have been introduced the last decade, but none of these have properties that allow a passing of the BBB to a satisfactory extent.

In this master thesis I have synthesized some known mono- and bispyridinium oximes according to literature protocol. Pralidoxime, a monopyridinium oxime and TMB- 4, a bispyridinium oxime, were successfully synthesized in high yields. TMB- 4 was synthesized via two different protocols, a direct route and a new, indirect route of synthesis. Potential oxime prodrugs were synthesized by reduction of mono- and bispyridinium oximes with NaBH4. Oximes that resisted reduction by NaBH4 were later attempted reduced using LiBH4. Other oximes were synthesized using new synthetic methods developed by the author. A new monopyridinium oxime was synthesized and isolated, whereas synthesis of bispyridinium derivatives of TMB- 4 proved difficult.