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

Abstract

Analogs of pralidoxime, which is a commercial antidote for intoxication from neurotoxic organophosphorus compounds, were designed, synthesized, characterized, and tested as potential inhibitors or reactivators of acetylcholinesterase (AChE) using the Ellman's test, nuclear magnetic resonance, and molecular modeling. These analogs include 1-methylpyridine-2-carboxaldehyde hydrazone, 1-methylpyridine-2-carboxaldehyde guanylhydrazone, and six other guanylhydrazones obtained from different benzaldehydes. The results indicate that all compounds are weak AChE reactivators but relatively good AChE inhibitors. The most effective AChE inhibitor discovered was the guanylhydrazone derived from 2,4-dinitrobenzaldehyde and was compared with tacrine, displaying similar activity to this reference material. These results indicate that guanylhydrazones as well as future similar derivatives may function as drugs for the treatment of Alzheimer's disease.

A new guanylhydrazone derivative as a potential acetylcholinesterase inhibitor for Alzheimer's disease: synthesis, molecular docking, biological evaluation and kinetic studies by nuclear magnetic resonance

“…In previous studies by our research group using molecular modeling and inhibition tests it has been found that the cationic site of guanylhydrazones are appropriate to interact with the anionic region of the AChE active site and compete with acetylcholine. 39,40 For this reason, a new guanylhydrazone (2) having some structural similarity with tacrine was prepared. Its guanidine group, a cationic group, can interact with the anionic site of the active site of the enzyme, and NMR results showed that this new guanylhydrazone is a more efficient inhibitor than tacrine.…”

Design, synthesis, structure, toxicology and in vitro testing of three novel agents for Alzheimer’s disease

“…To determine the capacities of these compounds to interact with HuAChE, docking was performed, 23 and the percentage inhibition of HuAChE was determined using Fig-NMR. 24,25 The toxicity was assessed in vivo using mice. 26,27 Concerning the synthesis, the reaction of 3-methoxy-2hydroxybenzaldehyde (1) and dimedone (2) afforded two possible compounds, 3 and 4, as shown in Scheme 2.…”

“…To experimentally conrm that compounds 5, 6 and 7 can inhibit HuAChE in vitro, the Fig-NMR method was performed, as described in two prior articles published by our research group. 24,25 The 1 H NMR spectrum of a solution containing pure AChE in the presence of ACh was recorded every 5 minutes for 110 minutes, providing 22 spectra. By looking at the relative amounts of ACh and its decomposition product, acetic acid, in the resultant spectra, it was possible to asses the ability of AChE to decompose ACh.…”

“…HuAChE was obtained from Sigma-Aldrich (1 mg), and the HuAChE inhibitions activities of compounds 5, 6 and 7 were determined by NMR using a 600 MHz spectrometer and 5 mm NMR tubes. The NMR method used for these inhibition tests was the Fig-NMR method, which was previously described in our articles on this topic, 24,25 and tacrine was used as the reference material. HuAChE was dissolved in 2 mL of deuterium oxide (D 2 O) containing 5% phosphate buffer at pH 7.4 in the 5 mm NMR tube; and the concentration of HuAChE was 0.2 mM in the presence of 1% of bovine serum albumin.…”

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

“…Acetylcholinesterase (AChE, EC. 3.1.1.7) is a crucial enzyme used to control transmission between neurons when the process is either mediated or modulated by the neurotransmitter acetylcholine (ACh) [64][65][66][67] . ACh is released by the axon terminal or varicosities of the transmitter neuron into the extracellular space to interact with the receptors of the other neuron.…”