Discovery of novel Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase inhibitors

Abstract

Based on its essential role in the life cycle of Trypanosoma cruzi, the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been considered a promising target for the development of novel chemotherapeutic agents for the treatment of Chagas' disease. In the course of our research program to discover novel inhibitors of this trypanosomatid enzyme, we have explored a combination of structure and ligand-based virtual screening techniques as a complementary approach to a biochemical screening of natural products using a standard biochemical assay. Seven natural products, including anacardic acids, flavonoid derivatives, and one glucosylxanthone were identified as novel inhibitors of T. cruzi GAPDH. Promiscuous inhibition induced by nonspecific aggregation has been discarded as specific inhibition was not reversed or affected in all cases in the presence of Triton X-100, demonstrating the ability of the assay to find authentic inhibitors of the enzyme. The structural diversity of this series of promising natural products is of special interest in drug design, and should therefore be useful in future medicinal chemistry efforts aimed at the development of new GAPDH inhibitors having increased potency.

Synthesis and Trypanocidal Properties of New Coumarin-Chalcone Derivatives

“…Some coumarins proved to be important molecules in the regression of the described pathology. Previous studies described that they act by inhibiting GAPDH (enzyme commission number 1.2.1.12), an important protein present in the trypanosomatids glycolytic pathway [14]. It has also been described that some coumarin derivatives are potent growth inhibitors of Leishmania amazonensis causing important changes in the parasite's ultrastructure such as mitochondrial swelling with concentric membranes in the mitochondrial matrix and intense exocytic activity in the region of the flagellar pocket [15].…”

Computational study of aromatic compounds inhibiting<em> Trypanosoma cruzi</em> glyceraldehyde 3-phosphate dehydrogenase

“…The computational study carried out in this work allowed a better view, at a molecular level, regarding the interaction of compounds [1][2][3][4][5][6] with the enzyme, showing that the compounds that have lower IC 50 also have more stable energy of drug-receptor binding. This result suggests that there is a more selective mechanism of interaction in GAPDH.…”

Quimioterapia da doença de Chagas: estado da arte e perspectivas no desenvolvimento de novos fármacos

“…Dentre estes, destacam-se as cumarinas (19,20), flavonoides (21) e ácidos anacárdicos (22) de origem natural; os derivados de produtos naturais como os análogos sintéticos do ácido anacardíaco (23); os compostos sintéticos derivados de planejamento racional como os nucleosídeos (24); os reativos intermediários de nitrogênio (óxido nítrico, nitroxil e peroxinirito) (25); e mais recentemente alguns complexos doadores de NO (26). [51][52][53][54][55][56] Metabolismo dependente de grupos tióis O principal mecanismo de defesa do T. cruzi contra o estresse oxidativo envolve os tióis tripanotiona (27), homotripanotiona (28), glutationa (29) e ovotiol (30) (Figura 6). 57 Tal hipótese é suportada pelo fato de que nenhuma catalase ou glutationa peroxidase é encontrada no parasita e a atividade da superóxido dismutase é muito reduzida.…”

“…70 Com base na premissa da suposta atividade inibitória promissora dos derivados N-óxidos (verdadeiros), foram sintetizados novos benzofuroxanos com o emprego de 2-nitropropano e piperidina (Figura 12). Esta estratégia sintética impossibilitou a formação de isômeros funcionais dos derivados 1,3-dióxido de 2H-benzimidazóis (47)(48)(49)(50)(51)(52) 70 De modo geral, esses resultados ilustram como a síntese orgânica planejada auxilia no desenvolvimento e otimização de propriedades biológicas de novos compostos bioativos.…”