Pyrano chalcones and a flavone from Neoraputia magnifica and their Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase-inhibitory activities

Abstract

The fruits of Neoraptua magnifica var. magnifica afforded three new flavonoids: 2′-hydroxy-4,4′,-dimethoxy-5′,6′-(2″,2″-dimethylpyrano)chalcone, 2′-hydroxy-3,4,4′-trimethoxy-5′,6′-(2″,2″-dimethylpyrano)chalcone, and 3′,4′-methylenedioxy-5,7-dimethoxyflavone which were identified on the basis of spectroscopic methods. The known flavonoids 2′-hydroxy-3,4,4′,5-tetramethoxy-5′,6′-(2″,2″-dimethylpyrano)chalcone, 2′-hydroxy-3,4,4′,5,6′-pentamethoxychalcone, 3′,4′-methylenedioxy-5,6,7-trimethoxyflavone, 3′,4′-methylenedioxy-5′,5,6,7-tetramethoxyflavone, 3′,4′,5′,5,7-pentamethoxyflavanone and 3′,4′,5′,5,7-pentamethoxyflavone were also identified. The latter flavone was the most active as glyceraldehyde-3-phosphate dehydrogenase-inhibitor

Introduction

As part of our continuous investigation into the chemical composition of Brazilian Neoraputia (Engler) Emmerich species, we recently reported the isolation of eight polymethoxylated flavones and one flavanone from N. alba (Engler) Emmerich (Arruda et al., 1991, Arruda et al., 1993), four polymethoxylated flavones, 2′-hydroxy-3,4,4′,5,6′-pentamethoxychalcone (1) and 2′-hydroxy-3,4,4′,5-tetramethoxy-5′,6′-(2″,2″-dimethylpyrano)chalcone (2) from N. magnifica var. magnifica (Engler) Emmerich (Passador et al., 1997). The isolation of these interesting new chalcones combined with our taxonomic interest in the Rutaceae stimulated an investigation of other organs of N. magnifica var. magnifica.

Chagas’ disease, caused by the protozoan Trypanosoma cruzi, is estimated to affect some 16–18 million people,mostly from South and Central America, where 25% of the total population is at risk (World Health Organization). Control of the insect vector (Triotoma infestans) in endemic areas has led to the virtual elimination of transmission by insect bites, and, as a consequence, blood transfusion and congenital transmission are currently the major causes for the spread of the disease. Besides low efficacy, the drugs currently available, nifurtimox and benzonidazole, have strong side effects (Souza et al., 1998). The bloodstream form of the parasite T. cruzi has no functional tricarboxylic acid cycle, and it is highly dependent on glycolysis for ATP production (Souza et al., 1998). This great dependence on glycolysis as a source of energy makes the glycolytic enzymes attractive targets for trypanocidal drug design. Thus, the three dimensional structure of the enzyme was determined (Souza et al., 1998). GAPDH catalyses the oxidative phosphorylation of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate. Glycosomal GAPDH shows potential target sites with significant differences compared with the homologous human enzyme, and inhibitors have been designed, synthesised, obtained from natural sources, and tested. In order to find blocking agents, chalcones and flavones isolated from N. magnifica were assayed and evaluated by interaction with the enzyme GAPDH from T. cruzi.