Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii.
ChemMedChem
; 8(7): 1138-60, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23776166
ABSTRACT
Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was used to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4' of the well-known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16 a and 16 c have IC50 values of 250â
nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26â
nM, respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130â
nM in the enzyme-based assay. With respect to their excellent inâ
vitro activity as well as improved drug-like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Toxoplasma
/
Triclosan
/
Toxoplasmose
/
Inibidores Enzimáticos
/
Enoil-(Proteína de Transporte de Acila) Redutase (NADH)
/
Antiprotozoários
Limite:
Animals
/
Humans
Idioma:
En
Revista:
ChemMedChem
Assunto da revista:
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos