Application of the Ugi Multicomponent Reaction in the Synthesis of Reactivators of Nerve Agent Inhibited Acetylcholinesterase

Recently, a new class
of reactivators of chemical warfare agent
inhibited acetylcholinesterase (AChE) with promising in vitro potential
was developed by the covalent linkage of an oxime nucleophile and
a peripheral site ligand. However, the complexity of these molecular
structures thwarts their accessibility. We report the compatibility
of various oxime-based compounds with the use of the Ugi multicomponent
reaction in which four readily accessible building blocks are mixed
together to form a product that links a reactivating unit and a potential
peripheral site ligand. A small library of imidazole and imidazolium
reactivators was successfully synthesized using this method. Some
of these compounds showed a promising ability to reactivate AChE inhibited
by various types of CWA in vitro. Molecular modeling was used to understand differences in reactivation
potential between these compounds. Four compounds were evaluated in
vivo using sarin-exposed rats. One of the reactivators showed improved
in vivo efficacy compared to the current antidote pralidoxime (2-PAM).