Bharate Sandip B, Guo Lilu, Reeves Tony E, Cerasoli Douglas M, Thompson Charles M
NIH COBRE Center for Structural and Functional Neuroscience, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT 59812, USA.
Bioorg Med Chem Lett. 2009 Sep 1;19(17):5101-4. doi: 10.1016/j.bmcl.2009.07.035. Epub 2009 Jul 10.
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(2)COOH 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.
报道了一系列带有杂环侧链或功能化脂肪族侧链的单季铵吡啶肟的制备及其对被对氧磷抑制的电鳗乙酰胆碱酯酶（EeAChE）和重组人乙酰胆碱酯酶（rHuAChE）进行再活化的相应体外评估。几种新合成的化合物能有效地使被抑制的EeAChE再活化，但对被抑制的rHuAChE的再活化效果较差。与带有呋喃和异恶唑杂环的化合物（在10⁻⁵M时，对EeAChE的再活化率为0 - 8%，对rHuAChE的再活化率为2 - 3%）相比，侧链带有噻吩环的化合物（20、23、26和29）表现出更好的再活化效果（对EeAChE的再活化率为24 - 37%，对rHuAChE的再活化率为5 - 9%）。N - 吡啶基 - CH₂COOH类似物8在10⁻⁴M时能使EeAChE（再活化率为36%）和rHuAChE（再活化率为15%）再活化，其再活化速率常数（k(r)）值对rHuAChE而言优于碘解磷定（2 - PAM）。
