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

Autor: Soares FA; Grupo de Química Medicinal do Instituto de Química de São Carlos, da Universidade de São Paulo, Av. Trabalhador Sancarlense, 400, 13566-590 Carlos/SP, Brazil., Sesti-Costa R, da Silva JS, de Souza MC, Ferreira VF, Santos Fda C, Monteiro PA, Leitão A, Montanari CA
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Aug 15; Vol. 23 (16), pp. 4597-601. Date of Electronic Publication: 2013 Jun 24.
DOI: 10.1016/j.bmcl.2013.06.029
Abstrakt: 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.
(Copyright © 2013 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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