New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds

Sabrina Heng, William Tieu, Stephanie Hautmann, Kevin Kuan, Daniel Sejer Pedersen, Markus Pietsch, Michael Gütschow, Andrew D. Abell

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7453-7463
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number24
DOIs
Publication statusPublished or Issued - 15 Dec 2011

Keywords

  • Acetylcholinesterase
  • Cholesterol esterase
  • Privileged scaffolds
  • Rhodanine
  • Thiazolidinedione

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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