Molecular design, synthesis and biological evaluation of 1,4-dihydro-4-oxoquinoline ribonucleosides as TcGAPDH inhibitors with trypanocidal activity.
Bioorg Med Chem Lett
; 23(16): 4597-601, 2013 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-23850203
ABSTRACT
The 1,4-dihydro-4-oxoquinoline ribonucleoside, Neq135, is the first low micromolar trypanosomatidae inhibitor to show good ligand efficiency (0.28 kcal mol(-1)atom(-1)) and good ligand lipophilicity efficiency (0.37 kcal mol(-1)atom(-1)) when acting against Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH). This and other six ribonucleosides were synthesized using our in-house technology, and assayed against the GAPDH NAD(+) site using isothermal titration calorimetry (ITC). Compound Neq135 had acceptable in vitro cytotoxicity, inhibited TcGAPDH with a Ki(app) value of 16 µM and killed the trypomastigote form of Trypanosoma cruzi Tulahuen strain with a concentration similar to that displayed by the control drug benznidazole. Neq135 is tenfold lower kinetic affinity against hGAPDH and does not kill Balb-c fibroblast nor spleen mouse cells. These results emphasize the possibility of integrating ligand- and target-based designs to uncover potent and selective TcGAPDH inhibitors that expands the opportunity for further medicinal chemistry endeavor towards NAD(+) TcGAPDH site.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ribonucleosídeos
/
Tripanossomicidas
/
Trypanosoma cruzi
/
Desenho de Fármacos
/
Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article