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

• Published in: Bioorganic & medicinal chemistry letters 2009-09, Vol.19 (17), p.5101-5104
• Main Authors: Bharate, Sandip B., Guo, Lilu, Reeves, Tony E., Cerasoli, Douglas M., Thompson, Charles M.
• Format: Article
• Language: English
• Subjects: 2-PAM; Acetylcholinesterase; Acetylcholinesterase - genetics; Acetylcholinesterase - metabolism; Animals; Biological and medical sciences; Cholinesterase Inhibitors - pharmacology; Cholinesterase Reactivators - chemical synthesis; Cholinesterase Reactivators - chemistry; Cholinesterase Reactivators - pharmacology; Electrophorus; Humans; Medical sciences; Monoquaternary pyridinium oximes; Organophosphorus; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; Paraoxon - pharmacology; Pesticides, fertilizers and other agrochemicals toxicology; Pralidoxime; Pralidoxime Compounds - chemical synthesis; Pralidoxime Compounds - chemistry; Pralidoxime Compounds - pharmacology; Reactivators; Recombinant Proteins - metabolism; Toxicology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.07.035

The synthesis and reactivation potency of new series of monoquaternary pyridinium oximes is reported. 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-CH 2COOH analog 8 reactivated EeAChE (36%) and rHuAChE (15%) at 10 −4 M with a k r value better than 2-pyridine aldoxime methiodide (2-PAM) for rHuAChE.