title: Molecular design, synthesis and biological evaluation of 1,4-dihydro-4-oxoquinoline ribonucleosides as TcGAPDH inhibitors with trypanocidal activity.
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.
authors.affiliation: 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.
authors.forename: Fabyana A
authors.initials: FA
authors.lastname: Soares
authors.forename: Renata
authors.initials: R
authors.lastname: Sesti-Costa
authors.forename: João Santana
authors.initials: JS
authors.lastname: da Silva
authors.forename: Maria Cecília B V
authors.initials: MC
authors.lastname: de Souza
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
authors.forename: Fernanda da C
authors.initials: Fda C
authors.lastname: Santos
authors.forename: Patricia A U
authors.initials: PA
authors.lastname: Monteiro
authors.forename: Andrei
authors.initials: A
authors.lastname: Leitão
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Montanari
mesh_terms: D042462:4-Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D041702:BALB 3T3 Cells; D015195:Drug Design; D005347:Fibroblasts / Q000187:drug effects; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D051379:Mice; D009593:Nitroimidazoles / Q000737:chemistry / Q000494:pharmacology; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D042462:4-Quinolones; D009593:Nitroimidazoles; D012263:Ribonucleosides; D014344:Trypanocidal Agents; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C009999:benzonidazole
keywords: Chagas disease; GAPDH; Isothermal titration calorimetry; Trypanosoma cruzi