Synthesis, Structure, and Antileishmanial Activity of Novel 1,2,4‐Trioxolanes, 1,2,4,5‐Tetraoxanes and Their Respective Deoxygenated Controls

Abstract

Given the reluctance of pharmaceutical companies to invest in new antileishmanial drugs, due to high costs and low perspectives of financial return, there is growing interest in repurposing existing drugs, often a more cost‐effective and quicker strategy to launch effective therapeutic solutions. Artemisinins, used as first‐line malaria treatments, have attracted attention for their potential activity against Leishmania. The mechanisms by which artemisinins treat malaria were deeply investigated and are thought to involve peroxide cleavage with formation of radicals, alkylating molecular targets within Plasmodium. However, the action of endoperoxides on Leishmania spp. remains poorly understood. To gain insight, we undertook the synthesis and structural characterization of 1,2,4‐trioxolanes, 1,2,4,5‐tetraoxanes, and respective deoxygenated controls. The compounds were evaluated in vitro against axenic and intracellular forms of Leishmania donovani and Leishmania major. Their selectivity indexes (SIs) were determined. Among 29 compounds, tetraoxanes 27, 29, 30, 32, and 33 exhibited the highest potency against both Leishmania species, but most showed limited selectivity (SI < 10) toward the parasite. Nevertheless, 33 demonstrated strong efficacy against L. major (SI of 13.7). Comparing peroxides versus their ether controls often revealed similar activities, suggesting involvement of other mechanisms beyond the iron‐dependent peroxide activation, unlike what is described for Plasmodium.