Synthesis, Biological Activity, and Docking Studies of New Acetylcholinesterase Inhibitors of the Bispyridinium Type

Abstract

A novel series of acetylcholinesterase (AChE) inhibitors of the bispyridinium type was synthesized and the inhibitory activity against AChE and butyrylcholinesterase (BChE) measured. In essence, the substitution pattern influenced the inhibitory potency against AChE, where the most active bispyridiniumoxime (TMB-4) was bisbenzyl substituted followed by monobenzyl substituted, bismethyl substituted, and unsubstituted derivatives of TMB-4. Hence, the bisbenzyl ether of TMB-4 was further investigated. In order to obtain diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so-called DUO series), the lateral ring substitution was systematically varied. The lowest IC(50) value against AChE found thus far in the DUO series was 0.34 microM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified by these investigations. In this binding mode, the docked ligands span the narrow, deeply buried active-site gorge, interacting with Trp84 at the bottom of the gorge, Tyr334 or Phe331 halfway down the gorge, and Trp279 at the peripheral anionic site at the mouth of the gorge. For specific ligands, additional interactions were found which helped to explain their deviating activity. Based on the promising characteristics of the novel acetylcholinesterase inhibitors presented, a series of structurally related, optimized candidates will be developed.

Synthesis, Biological Evaluation and Molecular Docking Study of Hydrazone-Containing Pyridinium Salts as Cholinesterase Inhibitors

“…Biological Activities Inhibitory activities of the target compounds against AChE and BuChE enzymes were evaluated by modified Ellman's spectrophotometric method. 9,25) Galantamine was used as reference standard. The results were summarized in Table 1 4.38 µM, respectively.…”

“…[5][6][7][8][9][10] In addition, quaternary nitrogen cation displays highly positive binding stabilization due to cation-π interactions with amino acid residues in AChE enzyme. [9][10][11][12] Many reports indicated that compounds bearing aromatic/ heteroaromatic rings on lateral parts of pyridinium displayed high AChE inhibitory activity and act as dual binding inhibitors.…”

“…[5][6][7][8][9][10] In addition, quaternary nitrogen cation displays highly positive binding stabilization due to cation-π interactions with amino acid residues in AChE enzyme. [9][10][11][12] Many reports indicated that compounds bearing aromatic/ heteroaromatic rings on lateral parts of pyridinium displayed high AChE inhibitory activity and act as dual binding inhibitors. [13][14][15][16] According to the docking studies of these compounds, it was found that both terminal rings attached to the pyridinium were able to bind simultaneously to both CAS and PAS of the enzyme resulting in higher AChE inhibitory activity.…”

Generation of small-compound libraries via random chemistry by Fenton’s reagent

“…of its possibility to inhibit acetylcholinesterase has been published so far. Hence, compound 4 was subjected to a modified Ellman's test 6 in order to check the inhibitory activity towards AChE. 4 inhibited AChE halfmaximally at IC 50 = 319 nM which is about three times higher than for 1-hydroxytacrine (IC 50 = 106 nM) and about 7 times higher than for tacrine (IC 50 = 44 nM), respectively.…”

Reactivation of sarin-inhibited pig brain acetylcholinesterase using oxime antidotes

“…There are many research studies dealing with the quantitative structure activity relationship (QSAR) [28][29][30]. QSAR uses structural patterns (position and number of oxime groups, presence and number of quaternary nitrogen) and physico-chemical properties (partition coefficient, pK a ) for predicting the biological activity of a proposed AChE reactivator [31]. However, none of them are able to accurately predict the most active, desired structure.…”