Synthesis, Electrochemistry, In Vitro Antiprotozoal Efficacy and Mechanistic Study of Novel ‘Ferrantoin’ and Related Derivatives

Abstract

African trypanosomiasis and leishmaniasis are vector-borne infectious diseases that affect both humans and animals. If left untreated, these neglected tropical diseases can be fatal. There are tens to thousands of new cases of both diseases reported by the WHO annually. The clinically available treatments are not practical because they suffer from severe adverse effects, impractical administration and increased instances of parasitic resistance. This emphasises the need for the development of new drugs to treat these diseases. In the search for such drugs, we investigated a series of ferrocenyl-based hydantoin/rhodanine derivatives. Herein, we report the design, synthesis, electrochemistry and in vitro biological activity of these derivatives against amastigotes of Leishmania donovani, as well as blood-stage trypomastigotes of Trypanosoma brucei brucei, Trypanosoma brucei gambiense, Trypanosoma brucei rhodesiense, Trypanosoma equiperdum and Trypanosoma evansi. Ferrocenylrhodanine analogues 19 and 23 were identified as a potential leishmanicidal early lead and hit, respectively, whereas 3-hydantoin-containing analogue 11 was identified as an antileishmanial hit. Ferrocene derivatives 23 and 11 were tested for ROS activity, and mitochondrial dysfunction is suspected to play a role in their mechanisms of action. Nine trypanosomacidal hits were also identified, of which ferrocenylrhodanine analogue 21 was the most prominent. These compounds are accordingly suited for further investigation as antitrypanosomatid drugs in the future. This may include increasing compound stability and solubility.