Department of Chemistry and Physics, The University of Adelaide, North Terrace, SA 5005, Australia.
Bioorg Med Chem. 2011 Dec 15;19(24):7453-63. doi: 10.1016/j.bmc.2011.10.042. Epub 2011 Oct 20.
We present a new class of inhibitors of pancreatic cholesterol esterase (CEase) based on 'priviledged' 5-benzylidenerhodanine and 5-benzylidene-2,4-thiazolidinedione structural scaffolds. The lead structures (5-benzylidenerhodanine 4a and 5-benzylidene-2,4-thiazolidinedione 4b) were identified in an in-house screening and these inhibited CEase with some selectivity over another serine hydrolase, acetylcholinesterase (AChE) (4a, CEase IC(50)=1.76 μM vs AChE IC(50)=5.14 μM and 4b, CEase IC(50)=5.89 μM vs AChE IC(50) >100 μM). A small library of analogs (5a-10a) containing a core amino acid in place of the glycerol group of the lead structures, was prepared to explore other potential binding interaction with CEase. These analogs inhibited CEase with IC(50) values ranging from 1.44 to 85 μM, with the majority exhibiting some selectivity for CEase versus AChE. The most potent compound of the library (10a) had 17-fold selectivity over AChE. We also report molecular docking (with CEase) and detailed kinetic analysis on the amino acid analogs to further understand the associated structure-activity relationships.
我们提出了一类新的胰腺胆固醇酯酶（CEase）抑制剂，基于“特权”5-苯亚甲基-4-噻唑烷酮和 5-苯亚甲基-2,4-噻唑烷二酮结构骨架。在内部筛选中确定了先导结构（5-苯亚甲基-4-噻唑烷酮 4a 和 5-苯亚甲基-2,4-噻唑烷二酮 4b），它们对另一种丝氨酸水解酶乙酰胆碱酯酶（AChE）具有一定的选择性（4a，CEase IC50=1.76 μM 对 AChE IC50=5.14 μM 和 4b，CEase IC50=5.89 μM 对 AChE IC50 >100 μM）。我们制备了一个包含先导结构中甘油基团的核心氨基酸的类似物（5a-10a）的小文库，以探索与 CEase 可能存在的其他潜在结合相互作用。这些类似物抑制 CEase 的 IC50 值范围为 1.44 至 85 μM，其中大多数对 CEase 相对于 AChE 具有一定的选择性。文库中最有效的化合物（10a）对 AChE 的选择性为 17 倍。我们还报告了氨基酸类似物的分子对接（与 CEase）和详细的动力学分析，以进一步了解相关的结构-活性关系。
