New cholesterol esterase inhibitors based on rhodanine and thiazolidinedione scaffolds.
Bioorg Med Chem
; 19(24): 7453-63, 2011 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-22075233
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Rodanina
/
Esterol Esterase
/
Tiazolidinedionas
/
Inibidores Enzimáticos
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article