Design, synthesis, electrochemistry and anti-trypanosomatid hit/lead identification of nitrofuranylazines

Chagas disease and leishmaniasis are vector-borne infectious diseases affecting both humans and animals. These neglected tropical diseases can be fatal if not treated. Hundreds to thousands of new Chagas disease and leishmaniasis cases are being reported by the WHO every year, and currently available treatments are insufficient. Severe adverse effects, impractical administrations and increased pathogen resistance against current clinical treatments underscore a serious need for the development of new drugs to curb these ailments. In search for such drugs, we investigated a series of nitrofuran-based azine derivatives. Herein, we report the design, synthesis, electrochemistry, and biological activity of these derivatives against promastigotes and amastigotes of Leishmania major, and L. donovani strains, as well as epimastigotes and trypomastigotes of Trypanosoma cruzi. Two leishmanicidal early leads and one trypanosomacidal hit with submicromolar activity were uncovered and stand for further in vivo investigation in the search for new antitrypanosomatid drugs. Future objective will focus on the identification of involved biological targets with the parasites.

Automated summary

Chagas disease and leishmaniasis are neglected tropical diseases with increasing numbers of reported cases. Current treatments are inadequate, highlighting the need for new drugs. In this study, nitrofuran-based azine derivatives were investigated for their potential as antitrypanosomatid drugs, revealing two early leads for leishmanicidal activity and one hit for trypanosomacidal activity that warrant further investigation in vivo.