Send to

Choose Destination
See comment in PubMed Commons below
Bioorg Med Chem Lett. 2013 Aug 15;23(16):4597-601. doi: 10.1016/j.bmcl.2013.06.029. Epub 2013 Jun 24.

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

Author information

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.


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.


Chagas disease; GAPDH; Isothermal titration calorimetry; Trypanosoma cruzi

[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center