The preparation, in vitro screening and molecular docking of symmetrical bisquaternary cholinesterase inhibitors containing a but-(2E)-en-1,4-diyl connecting linkage.

Abstract

Carbamate inhibitors (e.g. pyridostigmine bromide) are used as a pre-treatment for the prevention of organophosphorus poisoning. They work by blocking the native function of acetylcholinesterases (AChE) and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for their many undesirable side effects related to the carbamylation of AChE. In this paper, we describe 17 novel bisquaternary compounds and have analysed their effect on AChE inhibition. The newly prepared compounds were evaluated in vitro using both human erythrocyte AChE and human plasmatic butyrylcholinesterase. Their inhibitory ability was expressed as the half maximal inhibitory concentration (IC₅₀) and then compared to the standard carbamate drugs and two AChE reactivators. One of these novel compounds showed promising AChE inhibition in vitro (nM range) and was better than the currently used standards. Additionally, a kinetic assay confirmed the non-competitive inhibition of hAChE by this novel compound. Consequently, the docking results confirmed the apparent π-π or π-cationic interactions with the key amino acid residues of hAChE and the binding of the chosen compound at the enzyme catalytic site.

• Authors: Kamil Musilek, Ruzena Pavlikova, Jan Marek, Marketa Komloova, Ondrej Holas, Martina Hrabinova, Miroslav Pohanka, Vlastimil Dohnal, Martin Dolezal, Frank Gunn-Moore, Kamil Kuca
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 26 Issue 2 Pg. 245-53 (Apr 2011) ISSN: 1475-6374 [Electronic] England
• PMID: 21406034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cholinesterase Inhibitors

Topics

• Binding Sites
• Catalytic Domain
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Enzyme Activation (drug effects)
• Erythrocytes (enzymology)
• Humans
• Inhibitory Concentration 50
• Models, Molecular
• Molecular Structure
• Spectrometry, Mass, Electrospray Ionization
• Structure-Activity Relationship