Discovery of inhibitors from Brazilian Cerrado plants as candidate lead compounds for Malaria

Malaria is a lethal parasitosis with worldwide prevalence and despite investments in the search for new drug therapies, a high mortality rate is still observed. In the search for new candidates for antimalarial drugs, the modulation of the glycolytic pathway has been explored as a target to inhibit the development of the parasite and fight the infection. The Plasmodium falciparum enolase enzyme (Pfeno) is an attractive target of the parasite’s glycolytic pathway that catalyzes the conversion of 2-phosphoglycerate (2PG) to phosphoenolpyruvate (PEP). This enzyme is also associated with other important cellular functions (moonlighting functions, non-glycolytic functions) due to the different biological compartments in which it is found. The group CIBFar/CEPID determined the 3D crystallographic structure of Pfeno together with its enzymatic complexes, whose structural differences with the human homologous enzyme will allow the search for new selective inhibitors. In view of the success of antimalarial drugs from Natural Products (NP) and that the Cerrado is a promising source of world biodiversity, this proposal aims to investigate the bioactive compounds of this important Brazilian biome against the parasite that causes Malaria. Some plant species were selected for enzymatic screening based on the reported antiplasmodial activities of the species or genus of these plants. Among these, the fruit and stem bark fractions of Qualea grandiflora (Vochysiaceae) were previously investigated, in collaboration between CIBFar-CEPID and LaBiOrg-UFG/RC, with promising in vitro results against Plasmodium falciparum culture (IC50 values between 1.2 ng/mL and 7.0 ng/mL) and in vivo (100% parasitemia reduction at 100 mg/kg after the fifth day of P. berghei infection). The most potent extracts will be subjected to experiments in hyphenated analytical techniques to high resolution mass spectrometry (CLUE-MS/MS) and phytochemical investigation will be performed using HPLC-DAD guided by 1H NMR. The isolated compounds will be investigated against Pfeno and against strains of P. falciparum (sensitive and resistant), as well as having their cytotoxicity and selectivity evaluated. Isolated compounds that show significant inhibition of the enzyme (IC50Pfeno < 1 µM) and parasite growth (IC50Pf < 1 µM) and show promising selectivity indexes (SI > 10) will be selected for in vivo studies to prove their efficacy in a model animal and confirmation of the discovery of new candidates for leading compounds for Malaria.

Drug-based Strategies
Product Development

Apr 2022 — Feb 2025

Brazil