Preparation, in vitro screening and molecular modelling of symmetrical 4-tert-butylpyridinium cholinesterase inhibitors--analogues of SAD-128.

Abstract

Carbamate inhibitors (e.g., pyridostimine bromide) are used as a pre-exposure treatment for the prevention of organophosphorus poisoning. They work by blocking acetylcholinesterase's (AChE) native function and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for many undesirable side-effects related to the carbamylation of AChE. In this Letter, 19 analogues of SAD-128 were prepared and evaluated as cholinesterase inhibitors. The screening results showed promising inhibitory ability of four compounds better to used standards (pralidoxime, obidoxime, BW284c51, ethopropazine, SAD-128). Four most promising compounds were selected for further molecular docking studies. The SAR was stated from obtained data. The former receptor studies were reported and discussed. The further in vivo studies were recommended in the view of OP pre-exposure treatment.

• Authors: Kamil Musilek, Jan Roder, Marketa Komloova, Ondrej Holas, Martina Hrabinova, Miroslav Pohanka, Vlastimil Dohnal, Veronika Opletalova, Kamil Kuca, Young-Sik Jung
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 1 Pg. 150-4 (Jan 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21144749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• Organophosphates
• Pyridinium Compounds
• SAD-128
• Acetylcholinesterase

Topics

• Acetylcholinesterase (chemistry, metabolism)
• Binding Sites
• Catalytic Domain
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Computer Simulation
• Models, Molecular
• Organophosphates (chemistry)
• Pyridinium Compounds (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship