New series of monoquaternary pyridinium oximes: Synthesis and reactivation potency for paraoxon-inhibited electric eel and recombinant human acetylcholinesterase

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Bharate, Sandip B.¹  Guo, Lilu²  Reeves, Tony E.³  Cerasoli, Douglas M.³  Thompson, Charles M.^1,2 

[1] Univ Montana, Dept Biomed & Pharmaceut Sci, Ctr Struct & Funct Neurosci, NIH,COBRE, Missoula, MT 59812 USA

[2] ATERIS Technol LLC, Missoula, MT 59802 USA

[3] USAMRICD, Div Res, Physiol & Immunol Branch, Aberdeen Proving Ground, MD 21010 USA

关键词: Organophosphorus;    Acetylcholinesterase;    Reactivators;    Monoquaternary pyridinium oximes;    Pralidoxime;    2-PAM;   

DOI  :  10.1016/j.bmcl.2009.07.035

来源: Elsevier

【 摘 要 】

The preparation of a series of monoquaternary pyridinium oximes bearing either a heterocyclic side chain or a functionalized aliphatic side chain and the corresponding in vitro evaluation for reactivation of paraoxon-inhibited electric eel acetylcholinesterase (EeAChE) and recombinant human acetylcholinesterase (rHuAChE) are reported. Several newly synthesized compounds efficiently reactivated inhibited EeAChE, but were poor reactivators of inhibited rHuAChE. Compounds bearing a thiophene ring in the side chain (20, 23, 26 and 29) showed better reactivation (24-37% for EeAChE and 5-9% for rHuAChE) compared to compounds with furan and isoxazole heterocycles (0-8% for EeAChE and 2-3% for rHuAChE) at 10(-5) M. The N-pyridyl-CH2COOH analog 8 reactivated EeAChE (36%) and rHuAChE (15%) at 10(-4) M with a kr value better than 2-pyridine aldoxime methiodide (2-PAM) for rHuAChE. (C) 2009 Elsevier Ltd. All rights reserved.

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