Discovery of Acridine and Marinoquinoline Derivatives as Plasmodium falciparum Inhibitors

Abstract

Malaria is a global public health problem, with high mortality rates, especially in African countries. In Brazil, malaria has a very significant impact In 2016, 118 thousand new cases were reported, an incidence that increased by around 50% in 2017, with 175 thousand new cases reported. In this scenario, new therapeutic alternatives with innovative mechanism of action are extremely needed. Glycolytic enzymes play important roles in the biology of Plasmodium spp. For example, in the intra-erythrocyte stages of Plasmodium falciparum, glycolysis is the main metabolic pathway for energy production. The enolase enzyme (EC 4.2.1.11) catalyzes the reversible interconversion of 2-phosphoglycerate into phosphoenolpyruvate. The enzyme exhibits non-glycolytic functions and was found associated with nucleus, digestive vacuole, cytoskeleton, anchored in membranes, plasma and involved in the process of cell invasion. Therefore, Pfeno is an attractive target for the development of new antimalarial. The main goal of this project is to discover new bioactive compounds for the treatment of malaria based on structure-activity relationship (SAR) studies on two series of inhibitors previously identified with potent activity and safety profile. The first series investigated will be the acridine derivatives, which was previously identified in the Malaria Box collection as a P. falciparum enolase inhibitor (Pfeno IC 50 = 225 ¼M) and inhibitor of the in vitro P. falciparum growth (EC 50 = 74 nM). The second series investigated will be the marinoquinoline derivatives, which were discovered as potent inhibitors against sensitive strains (EC 50 3D7 = 39 nM) and resistant (EC 50 K1 = 41 ¼M), as well as extremely selective inhibitors (SI> 6400). Methods and strategies in structural Molecular Biology and Medical Chemistry will be used for the design of compounds with optimized properties through the integration of organic synthesis, SAR and ligand structure (LBDD) and molecular targeting (SBDD) studies. The compounds will be evaluated in standardized biological assays against the parasite (sensitive and resistant strains) and the enzyme (Pfeno) for the determination of inhibitory potency and SAR studies. Compounds that show significant inhibition of parasite growth (EC 50 <100 nM), will be subject to proof of concept studies (P. berghei model) to determine the in vivo activity of the most promising compounds. The São Carlos Institute of Physics - USP has vast experience in medicinal chemistry and structural biology, where is established the headquarter of the Center for Research and Innovation in Biodiversity and Drugs (CIBFar-CEPID). Our Center has well-equipped facilities to conduct all the steps in this proposal. It is important to mention that the group is part of the associate laboratories of the not-for- profit organization Medicines for Malaria Venture (MMV), acting as active partner in the discovery of new antimalarial candidates.