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

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.