Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 53210 Pardubice, Czech Republic.
Molecules. 2011 Sep 5;16(9):7565-82. doi: 10.3390/molecules16097565.
A series of novel and highly active acetylcholinesterase and butyrylcholinesterase inhibitors derived from substituted benzothiazoles containing an imidazolidine-2,4,5-trione moiety were synthesized and characterized. The molecular structure of 1-(2,6-diisopropyl-phenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-imidazolidine-2,4,5-trione (3g) was determined by single-crystal X-ray diffraction. Both optical isomers are present as two independent molecules in the triclinic crystal system. The lipophilicity of the compounds was determined as the partition coefficient log K(ow) using the traditional shake-flask method. The in vitro inhibitory activity on acetylcholinesterase from electric eel and butyrylcholinesterase isolated from equine serum was determined. The inhibitory activity on acetylcholinesterase was significantly higher than that of the standard drug rivastigmine. The discussed compounds are also promising inhibitors of butyrylcholinesterase, as some of the prepared compounds inhibit butyrylcholinesterase better than the internal standards rivastigmine and galanthamine. The highest inhibitory activity (IC₅₀ = 1.66 μmol/L) corresponds to the compound 1-(4-isopropylphenyl)-3-[(R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethyl]imidazolidine-2,4,5-trione (3d). For all the studied compounds, the relationships between the lipophilicity and the chemical structure as well as their structure-activity relationships are discussed.
一系列新型且高活性的乙酰胆碱酯酶和丁酰胆碱酯酶抑制剂，是由含咪唑烷-2,4,5-三酮部分的取代苯并噻唑衍生而来，并对其进行了合成和表征。1-(2,6-二异丙基-苯基)-3-[(1R)-1-(6-氟-1,3-苯并噻唑-2-基)乙基]-咪唑烷-2,4,5-三酮（3g）的分子结构通过单晶 X 射线衍射确定。在三斜晶系中，两个光学异构体均以两个独立的分子存在。采用传统的摇瓶法测定了化合物的亲脂性，作为分配系数 log K(ow)。测定了电鳗乙酰胆碱酯酶和马血清中分离的丁酰胆碱酯酶的体外抑制活性。对乙酰胆碱酯酶的抑制活性明显高于标准药物加兰他敏。所讨论的化合物也是丁酰胆碱酯酶有希望的抑制剂，因为一些制备的化合物对丁酰胆碱酯酶的抑制作用优于内部标准加兰他敏和石蒜碱。最高抑制活性（IC₅₀=1.66 μmol/L）对应于 1-(4-异丙基苯基)-3-[(R)-1-(6-氟苯并[d]噻唑-2-基)乙基]咪唑烷-2,4,5-三酮（3d）。对于所有研究的化合物，讨论了亲脂性与化学结构以及它们的构效关系之间的关系。
