Székács A, Halarnkar P P, Olmstead M M, Prag K A, Hammock B D
Department of Entomology, University of California, Davis 95616.
Chem Res Toxicol. 1990 Jul-Aug;3(4):325-32. doi: 10.1021/tx00016a009.
A series of (alkylthio)trifluoropropanones containing a heterocyclic moiety was synthesized. The compounds were tested for in vitro inhibition of four hydrolytic enzymes including insect juvenile hormone esterase (JHE), eel acetylcholinesterase (AChE), yeast lipase (LP), and bovine alpha-chymotrypsin. The I50 values ranged from 10(-3) to 10(-7) M. 3-(2-Pyridylthio)-1,1,1-trifluoro-2-propanone was found to be the most potent inhibitor as compared to the other tested heterocyclic analogues with an I50 value of 98 nM against JHE from the fifth-instar larvae of Trichoplusia ni. Results from X-ray crystallography showed that the compound exists in a tetrahedral gem-diol form stabilized by an intramolecular hydrogen bond in the solid state. X-ray crystallography of a less potent inhibitor, 3-(4-pyridylthio)-1,1,1-trifluoro-2- propanone, showed that it also exists in the hydrated form, but it lacks an intramolecular hydrogen bond. These results provide indirect support that trifluoromethyl ketones are transition-state mimic inhibitors of esterases, and the bearing of the results on the transition-state mimic theory is discussed. The I50 values against AChE were in the micromolar range. Compounds containing a imidazolyl, triazolyl, and pyrimidyl moiety showed the highest inhibition of this enzyme. Differential selectivity of inhibition was associated with the bond distances between the nitrogen and the carbonyl group as in the natural substrate, when measured in the molecules in their minimal energy conformations. Inhibition of LP was moderate to weak, when compared to JHE and AChE. None of the tested compounds showed significant inhibition of alpha-chymotrypsin.(ABSTRACT TRUNCATED AT 250 WORDS)
合成了一系列含有杂环部分的（烷硫基）三氟丙酮。测试了这些化合物对四种水解酶的体外抑制活性，包括昆虫保幼激素酯酶（JHE）、鳗鱼乙酰胆碱酯酶（AChE）、酵母脂肪酶（LP）和牛α-胰凝乳蛋白酶。半数抑制浓度（I50）值范围为10⁻³至10⁻⁷ M。与其他测试的杂环类似物相比，3-（2-吡啶硫基）-1,1,1-三氟-2-丙酮是最有效的抑制剂，对粉纹夜蛾五龄幼虫的JHE的I50值为98 nM。X射线晶体学结果表明，该化合物在固态下以通过分子内氢键稳定的四面体偕二醇形式存在。效力较低的抑制剂3-（4-吡啶硫基）-1,1,1-三氟-2-丙酮的X射线晶体学表明，它也以水合形式存在，但缺乏分子内氢键。这些结果间接支持了三氟甲基酮是酯酶的过渡态模拟抑制剂，并讨论了这些结果对过渡态模拟理论的影响。对AChE的I50值在微摩尔范围内。含有咪唑基、三唑基和嘧啶基部分的化合物对该酶的抑制作用最强。当在其最低能量构象的分子中测量时，抑制的差异选择性与天然底物中氮和羰基之间的键距有关。与JHE和AChE相比，对LP的抑制作用为中度至弱。所测试的化合物均未显示出对α-胰凝乳蛋白酶的显著抑制作用。（摘要截短至250字）
