Discovery of Acridine and Marinoquinoline derivatives as Plasmodium falciparum inhibitors

Malaria is a global public health problem, with high mortality rates, especially in countries on the African continent. In Brazil, malaria has a very relevant impact, with 118,000 new cases reported in 2016, an incidence that increased by about 50% in 2017, with 175,000 new cases reported. In this scenario, new therapeutic alternatives with an innovative mechanism of action are extremely necessary. Glycolytic enzymes play important roles in the biology of Plasmodium spp. For example, in the intraerythrocyte stages of Plasmodium falciparum, the main metabolic pathway for obtaining energy is glycolysis. The enzyme enolase (EC 4.2.1.11), present in this pathway, catalyzes the reversible interconversion of 2-phosphoglycerate to phosphoenolpyruvate, and it was found that the enzyme is associated with the nucleus, digestive vacuole, cytoskeleton, anchored in membranes, in the plasma and involved in the process of cell invasion, exhibiting non-glycolytic functions. Therefore, Pfeno is an attractive target for the development of antimalarial drugs. The second series investigated will be marinoquinoline derivatives, which have shown to be potent inhibitors against sensitive (EC50_3D7 = 39 nM) and resistant (EC50_K1 = 41 µM) strains, as well as extremely selective inhibitors (SI > 6400). Methods and strategies in structural molecular biology and medicinal chemistry will be used to design compounds with optimized properties through the integration of studies in organic synthesis, SAR and design based on ligand structure (LBDD) and molecular target (SBDD). The compounds will be evaluated in standardized biological assays against the parasite (sensitive and resistant strains) and enzymatic (Pfeno) to determine the inhibitory potency and SAR studies. For compounds that show significant inhibition of the Pfeno enzyme, crystallographic studies will be used to determine the mode of inhibitor binding and application of SBDD methods. The Institute of Physics of São Carlos – USP has vast experience in medicinal chemistry and structural biology, consecrated by the creation of the Center for Research and Innovation in Biodiversity and Pharmaceuticals (CIBFar-CEPID). Our Center has adequate facilities and equipment for the process of discovering new drug candidates, bringing together all the fundamental factors for carrying out the proposed project. It is important to mention that the group is part of the group of associated laboratories of the non-profit organization Medicines for Malaria Venture (MMV), acting as a partner of MMV in the discovery of new candidates for antimalarial drugs.

Project Details

Drug-based Strategies
Product Development

Jul 2018 — Feb 2022

Brazil