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

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]}

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

• 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