Previously we reported two salicylaldoxime conjugates (L7R3 and L7R5) showing equal or even higher reactivating efficiency for both organophosphorus nerve agent and pesticide inhibited acetylcholinesterase in comparison to obidoxime and HI-6. In this study, L7R3 and L7R5 were selected as lead compounds and refined by employing a fragment-based drug design strategy, and a total of 32 novel salicylaldoxime conjugates were constructed and screened for DFP and paraoxon inhibited acetylcholinesterase. The findings demonstrate that the conjugate L73R3, which contains a 4-nitrophenyl group, exhibited a higher reactivation efficacy against paraoxon-inhibited acetylcholinesterase compared to obidoxime and HI-6. It was confirmed that the combination of a 4-pyridinyl or 4-nitrophenyl peripheral site ligand, a piperazine linker and a methyl or chloro-substituted salicylaldoxime could construct efficient nonquaternary oxime reactivators. The results hold promise for developing a new generation of highly effective antidotes for organophosphate poisoning.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11042241 | PMC |
http://dx.doi.org/10.1039/d3md00628j | DOI Listing |
RSC Med Chem
April 2024
Department of Medicinal Chemistry, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences Beijing 100850 China
Previously we reported two salicylaldoxime conjugates (L7R3 and L7R5) showing equal or even higher reactivating efficiency for both organophosphorus nerve agent and pesticide inhibited acetylcholinesterase in comparison to obidoxime and HI-6. In this study, L7R3 and L7R5 were selected as lead compounds and refined by employing a fragment-based drug design strategy, and a total of 32 novel salicylaldoxime conjugates were constructed and screened for DFP and paraoxon inhibited acetylcholinesterase. The findings demonstrate that the conjugate L73R3, which contains a 4-nitrophenyl group, exhibited a higher reactivation efficacy against paraoxon-inhibited acetylcholinesterase compared to obidoxime and HI-6.
View Article and Find Full Text PDFBioorg Med Chem Lett
November 2023
Division of Bio and Drug Discovery, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, Republic of Korea. Electronic address:
This study aimed to explore non-pyridinium oxime acetylcholinesterase (AChE) reactivators that could hold the potential to overcome the limitations of the currently available compounds used in the clinic to treat the neurologic manifestations induced by intoxication with organophosphorus agents. Fifteen compounds with various non-pyridinium oxime moieties were evaluated for AChE activity at different concentrations, including aldoximes, ketoximes, and α-ketoaldoximes. The therapeutic potential of the oxime compounds was evaluated by assessing their ability to reactivate AChE inhibited by paraoxon.
View Article and Find Full Text PDFRSC Adv
September 2023
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences Tehran Iran
The present study aims to design and synthesise novel uncharged aldoximes and explore their reactivation abilities, structures, descriptors, and mechanisms of action, as well as assessing the interactions and stabilities in the active site of paraoxon-inhibited acetylcholinesterase enzyme using computational studies and assay. The comprehensive computational studies including quantum chemical, molecular dynamics simulations and molecular docking were conducted on paraoxon-inhibited human acetylcholinesterase to investigate the reactivation ability of the novel aldoximes and compare them with pralidoxime as a reactivator model molecule.
View Article and Find Full Text PDFInt J Mol Sci
November 2022
Institute for Medical Research and Occupational Health, Ksaverska c. 2, HR-10001 Zagreb, Croatia.
Seven pyridoxal dioxime quaternary salts (-) were synthesized with the aim of studying their interactions with human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The synthesis was achieved by the quaternization of pyridoxal monooxime with substituted 2-bromoacetophenone oximes (phenacyl bromide oximes). All compounds, prepared in good yields (43-76%) and characterized by 1D and 2D NMR spectroscopy, were evaluated as reversible inhibitors of cholinesterase and/or reactivators of enzymes inhibited by toxic organophosphorus compounds.
View Article and Find Full Text PDFMed Chem
January 2022
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Bijnor-Sisendi Road, Near CRPF Base Camp, Sarojini Nagar, Lucknow, Uttar Pradesh 226002, India.
Aim: To synthesize and evaluate the fused heterocyclic imidazo[1,2-a]pyridine based oxime as a reactivator against paraoxon inhibited acetylcholinesterase.
Background: Organophosphorus compounds (OPs) include parathion, malathion, chlorpyrifos, monocrotophos, and diazinon, which are commonly used in agriculture for enhancing agricultural productivity via killing crop-damaging pests. However, people may get exposed to OPs pesticides unintentionally/intentionally via ingestion, inhalation, or dermal.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!