title: New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds.
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.
authors.affiliation: Department of Chemistry and Physics, The University of Adelaide, North Terrace, SA 5005, Australia.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Heng
authors.forename: William
authors.initials: W
authors.lastname: Tieu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hautmann
authors.forename: Kevin
authors.initials: K
authors.lastname: Kuan
authors.forename: Daniel Sejer
authors.initials: DS
authors.lastname: Pedersen
authors.forename: Markus
authors.initials: M
authors.lastname: Pietsch
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D010179:Pancreas / Q000201:enzymology; D012236:Rhodanine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D045162:Thiazolidinediones; D012236:Rhodanine; C089946:2,4-thiazolidinedione; D002787:Sterol Esterase; D000110:Acetylcholinesterase