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A set of 23 steroidal 1,2,4,5-tetraoxane analogues were studied using quantum-chemical method (B3LYP/6-31 G*) and multivariate analyses (PCA, HCA, KNN and SIMCA) in order to calculate the properties and correlate them with antimalarial activity (log RA ) against Plasmodium falciparum clone D-6 from Sierra Leone. PCA results indicated 99.94% of the total variance and it was possible to divide the compounds into two classes: less and more active. Descriptors responsible for separating were: highest occupied molecular orbital energy (HOMO), bond length (O1-O2), Mulliken electronegativity (χ) and Bond information content (BIC0). We use HCA, KNN and SIMCA to explain relationships between molecular properties and biological activity of a training set and to predict antimalarial activity (log RA ) of 13 compounds (#24-36) with unknown biological activity. We apply molecular docking simulations to identify intermolecular interactions with a selected biological target. The results obtained in multivariate analysis aided in the understanding of the activity of the new compound's design (#24-36). Thus, through chemometric analyses and docking molecular study, we propose theoretical synthetic routes for the most promising compounds 28, 30, 32 and 36 that can proceed to synthesis steps and in vitro and in vivo assays.

Schistosomiasis ranks second only to malaria as the most common parasitic disease worldwide. 700 million people are at risk and 240 million are already infected. Praziquantel is the anthelmintic of choice but decreasing efficacy has already been documented. In this work, we exploited the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. A series of quinones (atovaquone derivatives and precursors) was evaluated regarding potency and selectivity against both SmDHODH and human DHODH. The best compound identified is 17 (2-hydroxy-3-isopentylnaphthalene-1,4-dione) with IC 50  = 23 ± 4 nM and selectivity index of 30.83. Some of the new compounds are useful pharmacological tools and represent new lead structures for further optimization., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Leishmaniasis is caused by protozoa of the genus Leishmania spp. and is considered the second most important protozoa in the world due to the number of cases and mortality. Despite its importance in terms of public health, the treatment of patients is limited and has mostly low levels of efficacy and safety. Farnesyl pyrophosphate synthase (FPPS) acts in the early stages of isoprenoid synthesis, and is important for maintaining the integrity of the lipid bilayer of the parasite that causes the disease. The aim of this work was to identify one potential inhibitor of the FPPS of Leishmania major through virtual screening by pharmacophore modeling and docking. A total of 85,000 compounds from a natural products database (ZINC 15 ) was submitted for virtual hierarchical screening, and the top ranked molecule in both methods was analyzed by intermolecular interaction profile and 20 ns molecular dynamics simulations. These results showed a promising compound from natural products that mimic the major interactions present in the substrate/inhibitor.