Discovery of Plasmodium falciparum inhibitors from Cerrado plants as candidate lead compounds for malaria: integrated studies of ultra-performance chromatography, spectroscopy and biological assays

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. Enolase (Pfeno) is an attractive target of the parasite’s glycolytic pathway, which 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 Pfeno is found. Recently our group (CIBFaR-CEPID) determined the 3D crystallographic structure of Pfeno along with its enzymatic complexes, whose structural differences with the human homologous enzyme will allow the search for new selective inhibitors. Some plant species were selected for enzymatic screening based on the reported antiplasmodic 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 results in vitro countercultures of Plasmodium falcipraum (IC50 values between 1.2 ng/mL and 7.0 ng/mL) and in vivo (100% reduction in parasitemia after the fifth day of infection by P. berghei) and with the identification of 32 compounds. LaBiOrg-UFG/RC has a significant sampling of Cerrado plant extracts that will be investigated in this proposal. The extracts will be evaluated against Pfeno and the most potent extracts will be submitted to experiments in hyphenated analytical techniques to high resolution mass spectrometry (CLUE-EM/EM). CLUE-MS/MS detection limit allows identifying minor compounds that may be responsible for the biological activity. Phytochemical investigation will be performed using HPLC-DAD guided by 1H NMR. The isolated compounds will be investigated against Pfeno and in P. falciparum (3D7 and K1) as well as their cytotoxicity and selectivity. Compounds that show significant inhibition of the enzyme and parasite growth will be selected as candidate lead compounds. 

Project details

Drug-based Strategies
Product Development

Jun 2021 — May 2023

Brazil