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  • PJ 34 br Introduction Malaria remains a serious parasitic di

    2021-07-23


    Introduction Malaria remains a serious parasitic disease in tropical areas due to its high morbidity and mortality rates. It is estimated that 212 million cases occurred globally in 2015, leading to 429, 000 deaths, most of which were in children aged under 5 years in Africa [1,2]. The protozoans Plasmodium falciparum and P. vivax are the main parasites responsible for this disease; the former, the most virulent, is responsible for 99% of the deaths. Resistance to antimalarial drugs has been observed as a consequence of genetic mutations and is a serious setback to antimalarial programs, since it limits the use of effective drugs like chloroquine [3] and artemisinin [4]. Therefore, discovery of new categories of antimalarial lead compounds is an important priority [5]. Quinones represent a large and important class of carbonyl-conjugated cyclic compounds with a great number of therapeutic applications. Naturally-occurring naphthoquinones are commonly found throughout different plant families, fungi and certain animals [6]. In this project, we started with lapachol (1) because it is a well-known antimalarial PJ 34 (see Fig. 1). Lapachol is a hydroxy-prenyl naphthoquinone occurring in woody trees of South American Bignoniaceae [5]. Lapachol has been studied as an interacting molecule with various protein targets such as plasmodial HSP70 [7], though in many studies its detailed mechanism of action is unknown and/or unreported [8]. It has been shown to interact with DHODH, but much more strongly with human DHODH (1 nM) than with PfDHODH (16 μM) [9]. Other modified lapachols, such as 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate, have shown better antimalarial activity than lapachol itself [[10], [11], [12]], showing the potential PJ 34 to improve upon lapachol in the search for new antimalarials. Atovaquone (2) is a synthetic hydroxy-naphthoquinone, structurally related to lapachol, which is very active against P. falciparum in both erythrocytic and liver stages of the protozoa life cycle and was introduced in malaria therapeutics in 2000. However, resistance was observed and it is presently used in association with other antimalarial drugs [13,14]. Atovaquone is also active against other protozoa parasites including Toxoplasma and Pneumocystis. It has been shown to be an inhibitor of coenzyme Q and ubiquinone (3), which play important roles in the parasitic respiratory chain, an effect that has been related to their structural similarities (see Fig. 1). Atovaquone blocks the mitochondrial electron transport chain, specifically targeting the cytochrome bc1 complex in the Plasmodium respirational system and further interfering in many processes including protein synthesis and heme biogenesis that are important for its survival [15,16]. A similar mechanism of action could be produced by lapachol and analogues, since they also have a naphthoquinone core [17]. Recent studies suggest a “cross-relation” between the respiratory chain and pyrimidine biosynthesis [15]. Following the availability of the complete parasite genome, it was realized that P. falciparum is dependent on de novo pyrimidine biosynthesis [18]. Thus, the parasite is also susceptible to the inhibition of dihydroorotate dehydrogenase (DHODH), a flavin-dependent mitochondrial enzyme that catalyzes the fourth and rate-limiting step in the de novo pyrimidine biosynthetic pathway [19,20]. Meanwhile, as demonstrated by reported X-ray co-crystal structures of human and plasmodial DHODHs bound to selective inhibitors, significant differences exist between the DHODHs from different species, in the whole sequence as well as among the amino acids forming the inhibitor binding site [18,21,22]. Therefore, P. falciparum DHODH (PfDHODH) represents a target for the discovery and development of parasite-specific inhibitors that could lead to promising antimalarial lead compounds [18,23]. Different chemical scaffolds have been identified as potent inhibitors of PfDHODH that show strong selectivity for the plasmodial DHODH over that of the human host [23,24]. A number of co-crystal structures of the human and PfDHODH with bound inhibitors are available in the RCSB Protein Data Bank (www.rcsb.org), and these have provided structural insights into key protein-ligand interactions governing the selective inhibition of PfDHODH [18,21,22]. Several computational studies have been done using various approaches with a goal of finding optimized PfDHODH inhibitors [25,26]. In this work, we applied molecular docking to explore binding modes as well as to provide important information about the quantitative structure-activity relationship (QSAR) for the new compounds' interaction with this enzyme. Additionally, the present results might support the proposal of more potent PfDHODH inhibitors [20,27] based on the lapachol pharmacophore.