Abstract
The chemical analysis of the sponge Dysidea avara afforded the known sesquiterpene quinone avarone, along with its reduced form avarol. To further explore the role of the thiazinoquinone scaffold as an antiplasmodial, antileishmanial and antischistosomal agent, we converted the quinone avarone into the thiazinoquinone derivative thiazoavarone. The semisynthetic compound, as well as the natural metabolites avarone and avarol, were pharmacologically investigated in order to assess their antiparasitic properties against sexual and asexual stages of Plasmodium falciparum, larval and adult developmental stages of Schistosoma mansoni (eggs included), and also against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Furthermore, in depth computational studies including density functional theory (DFT) calculations were performed. A toxic semiquinone radical species which can be produced starting both from quinone- and hydroquinone-based compounds could mediate the anti-parasitic effects of the tested compounds.
Highlights
Malaria and neglected tropical diseases (NTDs), a group of parasitic, bacterial, and viral infectious diseases (i.e., Schistosoma spp., Leishmania spp.), still have high morbidity and/or mortality rates worldwide
We developed this scaffold by creating of a chemical library of thiazinoquinone derivatives designed on the model of aplidinones, natural products isolated from a marine invertebrate (Figure 1)
Through an integrated experimental and theoretical approach, we demonstrated that the antiplasmodial and anticancer activity of a series of thiazinoquinone compounds was not related to their two electrons redox potential [11,12]
Summary
Malaria and neglected tropical diseases (NTDs), a group of parasitic, bacterial, and viral infectious diseases (i.e., Schistosoma spp., Leishmania spp.), still have high morbidity and/or mortality rates worldwide. In the frame of our research for new anti-parasitic chemical entities, we recently identified the thiazinoquinone scaffold as a novel chemotype active against both Plasmodium falciparum and Schistosoma mansoni [10,11,12,13,14] We developed this scaffold by creating of a chemical library of thiazinoquinone derivatives designed on the model of aplidinones, natural products isolated from a marine invertebrate (Figure 1). Based on the agent [11,13,14], we used the quinone avarone as chemical starting point to obtain the semisynthetic above described extensive exploration of the thiazinoquinone scaffold as antiplasmodial thiazinoquinone derivative, thiazoavarone (2, Figure 2). 2 resulted the most potent thiazinoquinone developed byofus,action highlighting quinone/hydroquinone/thiazinoquinone compounds corroborating the hypothesis that their the important role for the activity played by the substituent of the 1,1-dioxo-1,4-thiazine ring. Structure of avarone (1), the semisynthetic thiazoavarone (2) and avarol (3)
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