- Methyl Scanning and Revised Binding Mode of 2-Pralidoxime, an Antidote for Nerve Agent Poisoning
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Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food and Drug Administration for treating OPNA poisoning. However, 2-PAM is not centrally active due to its hydrophilicity and resulting poor blood-brain barrier permeability; hence, these deficiencies warrant the development of more hydrophobic analogs. Specifically, gaps exist in previously published structure activity relationship (SAR) studies for 2-PAM, thereby making it difficult to rationally design novel analogs that are concomitantly more permeable and more efficacious. In this study, we methodically performed a methyl scan on the core pyridinium of 2-PAM to identify ring positions that could tolerate both additional steric bulk and hydrophobicity. Subsequently, SAR-guided molecular docking was used to rationalize hydropathically feasible binding modes for 2-PAM and the reported derivatives. Overall, the data presented herein provide new insights that may facilitate the rational design of more efficacious 2-PAM analogs.
- Gambino, Adriana,Burnett, James C.,Koide, Kazunori
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p. 1893 - 1898
(2020/02/06)
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- Site-Selectivity in the Cyanation of 3-Substituted Pyridine 1-Oxides with Trimethylsilanecarbonitrile
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The cyanation of 3-halo-, 3-methoxy-, and 3-dimethylaminopyridine 1-oxide with trimethylsilanecarbonitrile gave predominantly the corresponding 3-substituted 2-pyridinecarbonitriles.The deoxygenation of nitropyridine 1-oxides to nitropyridines with the same reagent is also described.Keywords - site-selective reaction; trimethylsilanecarbonitrile; pyridine 1-oxide; 2-pyridine-carbonitrile; nitropyridine 1-oxide; deoxygenation; aromatic amine N-oxide; cyanation
- Sakamoto, Takao,Kaneda, Soh-ichi,Nishimura, Sumiko,Yamanaka, Hiroshi
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p. 565 - 571
(2007/10/02)
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