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Type: Journal article
Title: New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds
Author: Heng, S.
Tieu, W.
Hautmann, S.
Kuan, K.
Pedersen, D.
Pietsch, M.
Gutschow, M.
Abell, A.
Citation: Bioorganic and Medicinal Chemistry, 2011; 19(24):7453-7463
Publisher: Pergamon-Elsevier Science Ltd
Issue Date: 2011
ISSN: 0968-0896
Statement of
Sabrina Heng, William Tieu, Stephanie Hautmann, Kevin Kuan, Daniel Sejer Pedersen, Markus Pietsch, Michael Gütschow and Andrew D. Abell
Abstract: 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.
Keywords: Cholesterol esterase
privileged scaffolds
Rhodanine and Thiazolidinedione
Rights: © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.bmc.2011.10.042
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