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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Molecular design, synthesis and biological evaluation of 1,4-dihydro-4-oxoquinoline ribonucleosides as TcGAPDH inhibitors with trypanocidal activity

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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
[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

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