Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

Abstract

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

“…The third most effective compound is the paramethylated compound (8), and the less effective compounds are 5, which does not contain an R group, and 9 and 10, whose para-R groups, Me 2 N and HO, respectively, are electropositive. This information indicates that the best benzylidene guanylhydrazones for the inhibition of AChE should contain strong electron withdrawing R groups.…”

“…IR (cm À1 ): 3291 (amine N-H), 3119 (aromatic C-H), 1628-1505 (C ¼ N and C ¼ C), 1293 and 1247 (C-N), 780 (C-H out of plane (Di-1,2) General procedure for guanylhydrazones (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) Aminoguanidine hydrochloride (1.4 mmol) dissolved in 20 mL of 95% ethanol, the corresponding aldehyde (1 mmol) and two drops of HCl (0.6 M) were added to a 50.0 mL round-bottom flask. The solution was stirred and heated under reflux.…”

“…For this reason, AChE inhibitors are very important agents for the treatment of AD, but some of these inhibitors are toxic, such as tacrine, requiring the development of new agents. Interestingly, some AChE reactivators also display competitive inhibition of the enzyme 8 , and the reversible inhibitor and AD drug galantamine protects animals from soman, sarin, and paraoxon intoxication 9 , suggesting that novel compounds may have dual application, for AD and organophosphorus intoxication.…”

“…To reactivate inhibited and phosphorylated AChE, it is necessary to use agents with the appropriate capacity to execute a nucleophilic attack on the phosphorus atom bound to Ser203, leading to the reactivation of the function of this serine. The AChE reactivator agents are mainly cationic oximes 7 , which are effective but, unfortunately, not appropriate against all neurotoxic organophosphorus agents 8 , thereby necessitating the development of new and more effective agents for the protection of all humanity.…”

Synthesis and inhibitory properties of some carbamates on carbonic anhydrase and acetylcholine esterase

“…For this reason, AChE inhibitors are very important agents for the treatment of AD, but some of these inhibitors are toxic, such as tacrine, requiring the development of new agents. Interestingly, some AChE reactivators also display competitive inhibition of the enzyme 73 , and the reversible inhibitor and AD drug Galantamine protects animals from soman, sarin and paraoxon intoxication, suggesting that novel compounds may have dual application, for AD and organophosphorus intoxication 74 …”