Departamento de Química, Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais (NuBBE), Instituto de Química, UNESP-Universidade Estadual Paulista, C.P. 355, 14801-970, Araraquara, SP, Brazil.
Curr Med Chem. 2011;18(22):3423-30. doi: 10.2174/092986711796504718.
In the search for acetylcholinesterase inhibitors as a potential target for the discovery of anthelmintic drugs, a series of 27 pyridinic and pyrazinic compounds have been designed on the basis of molecular hybridization of two known AChE inhibitors, namely, tacrine and (-)-3-O-acetylspectaline, and on the concept of isosterism. The synthesized compounds generally presented moderate anticholinesterasic activities when compared with the positive control physostigmine, but one compound (ethyl 2-[(6-chloropyrazin-2-yl)sulfanyl] acetate) exhibited an in vitro ability to immobilize the root-knot nematode Meloidogyne incognita that was highly comparable to that of the positive control Temik. Moreover, in anthelmintic assays against the gastrointestinal parasitic nematode Nippostrongylus brasiliensis (L4), some of the compounds, such as (6-chloropyrazin-2-yl)sulfanyl ethanol (32, EC₅₀ = 33 nM), presented activities that were considerably stronger than that of the positive control albendazole (EC₅₀ = 340 nM). In the light of the positive results obtained in the anthelmintic evaluations, the acute oral toxicity of the representative compound diethyl 2,2'-[(3-nitropyridine-2,6-diyl) bissulfanediyl] diacetate was determined in rats, and the drug was shown to be non-toxic at a dose of 2000 mg/kg. These results, allied with the relatively simple structures of the active compounds and their facile synthesis, highlight their potential use as anthelmintic or nematicidic agents.
在寻找乙酰胆碱酯酶抑制剂作为发现驱虫药物的潜在目标的过程中，基于两种已知的 AChE 抑制剂即他克林和（-）-3-O-乙酰螺旋碱的分子杂交，并基于同型物原理，设计了一系列 27 种吡啶基和吡嗪基化合物。与阳性对照毒扁豆碱相比，合成的化合物通常表现出中等的抗胆碱酯酶活性，但有一种化合物（乙基 2-[(6-氯吡嗪-2-基)硫基]乙酸酯）具有体外固定根结线虫 Meloidogyne incognita 的能力，与阳性对照涕灭威相当。此外，在针对胃肠道寄生线虫旋毛虫（Nippostrongylus brasiliensis）（L4）的驱虫试验中，一些化合物，如（6-氯吡嗪-2-基）硫基乙醇（32，EC₅₀ = 33 nM），其活性明显强于阳性对照阿苯达唑（EC₅₀ = 340 nM）。鉴于驱虫评估中获得的积极结果，在大鼠中测定了代表性化合物二乙基 2,2'-[(3-硝基吡啶-2,6-二基)双硫代二乙酸酯的急性口服毒性，该药物在 2000 mg/kg 剂量下显示出非毒性。这些结果，加上活性化合物相对简单的结构及其易于合成的特点，突出了它们作为驱虫或杀线虫剂的潜在用途。
