1. 6-Methyluracil derivatives as peripheral site ligand-hydroxamic acid conjugates: Reactivation for paraoxon-inhibited acetylcholinesterase.
- Author
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Semenov VE, Zueva IV, Lushchekina SV, Lenina OA, Gubaidullina LM, Saifina LF, Shulaeva MM, Kayumova RM, Saifina AF, Gubaidullin AT, Kondrashova SA, Latypov SK, Masson P, and Petrov KA
- Subjects
- Animals, Brain enzymology, Dose-Response Relationship, Drug, Humans, Hydroxamic Acids chemistry, Ligands, Maze Learning drug effects, Mice, Molecular Docking Simulation, Molecular Structure, Paraoxon pharmacology, Paraoxon toxicity, Quantum Theory, Rats, Rats, Wistar, Structure-Activity Relationship, Uracil chemical synthesis, Uracil chemistry, Uracil pharmacology, Acetylcholinesterase metabolism, Cholinesterase Inhibitors pharmacology, Hydroxamic Acids pharmacology, Paraoxon antagonists & inhibitors, Uracil analogs & derivatives
- Abstract
New uncharged conjugates of 6-methyluracil derivatives with imidazole-2-aldoxime and 1,2,4-triazole-3-hydroxamic acid units were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. Using paraoxon (POX) as a model organophosphate, it was shown that 6-methyluracil derivatives linked with hydroxamic acid are able to reactivate POX-inhibited human acetylcholinesterase (AChE) in vitro. The reactivating efficacy of one compound (5b) is lower than that of pyridinium-2-aldoxime (2-PAM). Meanwhile, unlike 2-PAM, in vivo study showed that the lead compound 5b is able: (1) to reactivate POX-inhibited AChE in the brain; (2) to decrease death of neurons and, (3) to prevent memory impairment in rat model of POX-induced neurodegeneration., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2020
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