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

Abstract

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).

Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase

“…Novelo xime structures synthesized using the Ugi multicomponent reaction. [96] Chem.E ur.J. 2019, 25,5337 -5371 www.chemeurj.org tion of the cyclosarin-and tabun-inhibited hAChE;h owever, the pyridinium and imidazole oximes, in additiont ot he hydroxyiminoacetamides, were able to reactivate sarin-inhibited AChE.…”

“…The work of de Bruijn et al made use of am ulticomponent reaction, the Ugi reaction, to generate as mall diverse library of both charged and uncharged oxime reactivators of OP-inhibited AChE ( Figure 11). [96] The Ugi multicomponent reactioni sa condensation reaction that combinesa na ldehydeo rk etone, carboxylic acid, amine, and an isocyanide in as ingle reaction. Such ah ighly efficient reactiont hen allows the synthesis of a diversel ibrary of compounds rapidlya nd easily,a sw as exploited by de Bruijn et al In their work, the carboxylic acid moiety was attached to various oximes and possessed variousl inker lengths.…”

“…The work of de Bruijn et al. made use of a multicomponent reaction, the Ugi reaction, to generate a small diverse library of both charged and uncharged oxime reactivators of OP‐inhibited AChE (Figure ) . The Ugi multicomponent reaction is a condensation reaction that combines an aldehyde or ketone, carboxylic acid, amine, and an isocyanide in a single reaction.…”

In silico Study of Potential Non-oxime Reactivator for Sarin-inhibited Human Acetylcholinesterase

“…Apart from these interactions, (R)-Boc-nipecotic acid might also introduce as a carboxylic acid moiety source, which can be attached to various oximes that have been successfully proven as a potential antidote. A study carried out by de Koning et al (2017), which reported the…”

Discovery of Dihydropyrrol-2-ones as Novel G0/G1-Phase Arresting Agents Inducing Apoptosis

“…Multicomponent reaction (MCR) has advantages of atom economy, high efficiency, and fast building structural diversity and complexity of compound libraries − and becomes a powerful tool in drug synthesis and discovery. ,, Considering that heterocycles have diverse bioactivities, we are interested in their MCR synthesis − and bioactivities . Pyrrolidone rings are important heterocycles with a wide range of pharmacological activities, such as G0/G1-phase arresting agents VI .…”