Piazzi Lorna, Belluti Federica, Bisi Alessandra, Gobbi Silvia, Rizzo Stefano, Bartolini Manuela, Andrisano Vincenza, Recanatini Maurizio, Rampa Angela
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Bioorg Med Chem. 2007 Jan 1;15(1):575-85. doi: 10.1016/j.bmc.2006.09.026. Epub 2006 Sep 27.
In this work, we further investigated a previously introduced class of cholinesterase inhibitors. The removal of the carbamic function from the lead compound xanthostigmine led to a reversible cholinesterase inhibitors 3. Some new 3-[omega-(benzylmethylamino)alkoxy]xanthen-9-one analogs were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The length of the alkoxy chain of compound 3 was increased and different substituents were introduced. From the IC(50) values, it clearly appears that the carbamic residue is crucial to obtain highly potent AChE inhibitors. On the other hand, peculiarity of these compounds is the high selectivity toward BuChE with respect to AChE, being compound 12 the most selective one (6000-fold). The development of selective BuChE inhibitors may be of great interest to clarify the physiological role of this enzyme and to provide novel therapeutics for various diseases.
在这项工作中，我们进一步研究了一类先前引入的胆碱酯酶抑制剂。从先导化合物黄夹苷中去除氨基甲酸官能团，得到了一种可逆性胆碱酯酶抑制剂3。设计、合成了一些新的3-[ω-(苄基甲基氨基)烷氧基]呫吨-9-酮类似物，并对其对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制活性进行了评估。增加了化合物3烷氧基链的长度，并引入了不同的取代基。从半数抑制浓度（IC50）值可以清楚地看出，氨基甲酰基残基对于获得高效的AChE抑制剂至关重要。另一方面，这些化合物的特点是对BuChE相对于AChE具有高选择性，化合物12是最具选择性的一种（6000倍）。开发选择性BuChE抑制剂对于阐明该酶的生理作用以及为各种疾病提供新型治疗方法可能具有重要意义。
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