Towards innovative tools against vector-borne diseases: focusing on Plasmodium and Leishmania spp.

Up to date, the World Health Organization (WHO) recognizes twenty conditions belonging to neglected tropical diseases (NTDs) caused by parasites, viruses, bacteria, and snake envenoming that affect some of the World’s poorest areas, predominantly in Africa, Asia, and the Americas. NTDs, that affect more than a billion people worldwide, are referred to as “neglected” as they receive inadequate attention, e.g., in terms of research funding, when compared to other diseases. Of the twenty NTDs recognized by the WHO, twelve are caused by parasites. Based on data provided by the 2019 Global Burden of Disease Study (GBD), over 20 million disability adjusted life years (DALYs) are caused by NTDs and approximately 750,000 people died because of NTDs and malaria. Taken together, these data lead malaria and NTDs to be the 15th leading cause of death worldwide. Regarding malaria, based on our previous study on bridged bicyclic 2,3-dioxabicyclo[3,3,1]dioxanes as antimalarial agents, in this work we aimed at improving the potency and the pharmacokinetic profiles of the latter by developing two new classes of bridged bicyclic endoperoxides. The introduction of protonable chains at R1 led to a marked increase in potency with respect to previous derivatives; additionally, the introduction of until-now unexplored triazine-based R1 substituents paved the way for the rational design of novel optimized antimalarial agents. Both classes of endoperoxides showed good inhibitory potency toward P. falciparum, and these results were also rationalized by in silico analysis of the interaction between the peroxide bridge and Fe(II)-heme. Furthermore, taking inspiration from the anticancer properties of ART-derived dimers, three new sets of endoperoxide-based dimers were designed and synthesized. The study design aimed at unveiling the main feature required for the explication of the antitumor activity. Preliminary biological investigation performed in human leukemia HL-60 cell line highlighted compounds 66d and 66g as the most promising derivatives of the series. In conclusion, 24 new chemical entities were synthesized and subjected to biological investigation. As per NTDs, we have identified 25 new chemical entities active against Leishmania (and possibly other trypanosomatids) trypanothione reductase, derived from the hit compound 138a. The potent and selective TR inhibitor 138a, identified by screening of GSK LeishBox, acts by selectively bind the TS2 binding pocket of TR (with respect to hGR). Further structural information were obtained by crystallography studies, which led to the resolution of the co-crystal structure of 138a in complex with TbTR, thus confirming the mechanism of inhibition. The intensive SAR analysis led to the identification of the most important features of the parent compound. The most promising derivatives, in terms of IC50 values against LiTR, were also evaluated in phenotypic assays against axenic amastigote and microphage-infecting promastigote life cycle stages of L. infantum. Moreover, the toxicity profile for some of the best compound was assessed in 3T3 and HepG2 cell lines to get preliminary information about the selectivity of the latter versus human hosts. Further biological studies are ongoing to validate the therapeutic potential of this new class of TR inhibitors in an in vivo murine model of Leishmania infection.