Oxime

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Fan Wu - One of the best experts on this subject based on the ideXlab platform.

Lei Xu - One of the best experts on this subject based on the ideXlab platform.

Rongliang Wang - One of the best experts on this subject based on the ideXlab platform.

John R Cashman - One of the best experts on this subject based on the ideXlab platform.

  • Nonquaternary reactivators for organophosphate-inhibited cholinesterases
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Jarosław Kalisiak, Erik C. Ralph, John R Cashman
    Abstract:

    A new class of amidine-Oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) was synthesized and tested in vitro and in vivo. Compared with 2-PAM, the most promising cyclic amidine-Oxime (i.e., 12e) showed comparable or greater reactivation of OP-inactivated AChE and OP-inactivated BChE. To the best of our knowledge, this is the first report of a nonquaternary Oxime that has, comparable to 2-PAM, in vitro potency for reactivation of Sarin (GB)-inhibited AChE and BChE. Amidine-Oximes were tested in vitro, and reactivation rates for OP-inactivated butyrylcholinesterase (BChE) were greater than those for 2-PAM or MINA. Amidine-Oxime reactivation rates for OP-inactivated acetylcholinesterase (AChE) were lower compared to 2-PAM but greater compared with MINA. Amidine-Oximes were tested in vivo for protection against the toxicity of nerve agent model compounds. (i.e., a model of Sarin). Post-treatment (i.e., 5 min after OP exposure, i.p,) with amidine Oximes 7a-c and 12a, 12c, 12e, 12f, and 15b (145 μmol/kg, i.p.) protected 100% of the mice challenged with the sarin model compound. Even at 25% of the initial dose of amidine-Oxime (i.e., a dose of 36 μmol/kg, i.p.), 7b and 12e protected 100% of the animals challenged with the sarin nerve agent model compound that caused lethality in 6/11 animals without amidine-Oxime.

  • Amidine-Oximes: reactivators for organophosphate exposure.
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Jarosław Kalisiak, Erik C. Ralph, Jun Zhang, John R Cashman
    Abstract:

    A new class of amidine−Oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) were designed, synthesized, and tested. These compounds represent a novel group of Oximes with enhanced capabilities of crossing the blood−brain barrier. Lack of brain penetration is a major limitation for currently used Oximes as antidotes of OP poisoning. The concept described herein relies on a combination of an amidine residue and Oxime functionality whereby the amidine increases the binding affinity to the ChE and the Oxime is responsible for reactivation. Amidine−Oximes were tested in vitro and reactivation rates for OP-BuChE were greater than pralidOxime (2-PAM) or monoisonitrosoacetone (MINA). Amidine−Oxime reactivation rates for OP-AChE were lower compared to 2-PAM but greater compared with MINA. After pretreatment for 30 min with Oximes 15c and 15d (145 μmol/kg, ip) mice were challenged with a soman model compound. In addition, 15d was tested in a post-treatment experiment (145 μmol/kg, ip, administ...

  • Amidine-Oximes: Reactivators for organophosphate exposure
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Jarosław Kalisiak, Erik C. Ralph, Jun Zhang, John R Cashman
    Abstract:

    A new class of amidine-Oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) were designed, synthesized, and tested. These compounds represent a novel group of Oximes with enhanced capabilities of crossing the blood-brain barrier. Lack of brain penetration is a major limitation for currently used Oximes as antidotes of OP poisoning. The concept described herein relies on a combination of an amidine residue and Oxime functionality whereby the amidine increases the binding affinity to the ChE and the Oxime is responsible for reactivation. Amidine-Oximes were tested in vitro and reactivation rates for OP-BuChE were greater than pralidOxime (2-PAM) or monoisonitrosoacetone (MINA). Amidine-Oxime reactivation rates for OP-AChE were lower compared to 2-PAM but greater compared with MINA. After pretreatment for 30 min with Oximes 15c and 15d (145 μmol/kg, ip) mice were challenged with a soman model compound. In addition, 15d was tested in a post-treatment experiment (145 μmol/kg, ip, administration 5 min after sarin model compound exposure). In both cases, amidine-Oximes afforded 100% 24 h survival in an animal model of OP exposure.

Jane Robertson - One of the best experts on this subject based on the ideXlab platform.

  • Oximes for acute organophosphate pesticide poisoning
    Cochrane Database of Systematic Reviews, 2011
    Co-Authors: N A Buckley, Marc Bevan, Michael Eddleston, Yi Li, Jane Robertson
    Abstract:

    Acute organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the developing world. Standard treatment involves administration of intravenous atropine and Oxime to reactivate inhibited acetylcholinesterase. The clinical usefulness of Oximes, such as pralidOxime and obidOxime, has been challenged over the past 20 years by physicians in many parts of the world.