| Full text | |
| Author(s): |
Soares, Fabyana A.
[1, 2]
;
Sesti-Costa, Renata
[3]
;
da Silva, Joao Santana
[3]
;
de Souza, Maria Cecilia B. V.
[4]
;
Ferreira, Vitor F.
[4]
;
Santos, Fernanda da C.
[4]
;
Monteiro, Patricia A. U.
[2]
;
Leitao, Andrei
[2]
;
Montanari, Carlos A.
[1, 2]
Total Authors: 9
|
| Affiliation: | [1] Univ Fed Sao Carlos, Dept Quim, BR-13565905 Sao Carlos, SP - Brazil
[2] Univ Sao Paulo, Grp Quim Med, Inst Quim Sao Carlos, BR-13566590 Carlos, SP - Brazil
[3] Univ Sao Paulo, Dept Bioquim & Imunol, Fac Med Ribeirao Preto, BR-14049900 Ribeirao Preto, SP - Brazil
[4] Univ Fed Fluminense, Inst Quim, Dept Quim Organ, BR-24020150 Niteroi, RJ - Brazil
Total Affiliations: 4
|
| Document type: | Journal article |
| Source: | Bioorganic & Medicinal Chemistry Letters; v. 23, n. 16, p. 4597-4601, AUG 15 2013. |
| Web of Science Citations: | 17 |
| 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 K-i(app) value of 16 mu M 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. (C) 2013 Elsevier Ltd. All rights reserved. (AU) | |
| FAPESP's process: | 11/07025-3 - In silico studies and cell-based assays to identify new therapeutic approaches to prostate cancer |
| Grantee: | Andrei Leitão |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 11/01893-3 - Optimizing trypanosomatid agents by integration of in silico, calorimetry and cell-based assays |
| Grantee: | Carlos Alberto Montanari |
| Support Opportunities: | Regular Research Grants |