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Basic Information

ID: ALA2407047

Journal: Bioorg Med Chem Lett

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

Authors: Soares FA, Sesti-Costa R, da Silva JS, de Souza MC, Ferreira VF, Santos Fda C, Monteiro PA, Leitão A, Montanari CA.

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.

CiteXplore: 23850203

DOI: 10.1016/j.bmcl.2013.06.029