Biological activity and structure-activity relationship of functionalized thiols against Leishmania major, the agent of human cutaneous leishmaniasis

Abstract

Abstract Leishmania are protozoan parasites causing a spectrum of pathologies in humans grouped under the name leishmaniasis. Clinical outcomes range from the self-healing cutaneous form to the visceral one that is fatal in the absence of treatment. The leishmaniases are endemic in 98 countries in the tropics, subtropics, and southern Europe where 3 million new cases and more than 50,000 deaths are recorded yearly. The control of the disease is challenging with no approved vaccine coupled with toxic chemotherapeutics and development of parasite resistance to some available drugs. It is therefore evident that identification of new control methods including new therapeutics should be strongly encouraged. In the present study, thiol organic compounds were synthesized and tested for their activity against Leishmania major, the causative agent of human cutaneous leishmaniasis. Of the 21 compounds tested, 13 were active against L. major promastigotes in vitro at 100 µg/mL. Selected compounds tested in a dose-response assay showed activity at concentration as low as 25 µg/mL, a level of activity similar to that of Amphotericin B, a drug of choice for the treatment of human leishmaniasis. Structure-activity analysis shows that the addition of certain substituents such as a methoxy group to a compound that was biologically active renders it inactive. Together, our data demonstrate that functionalized thiols have in vivo anti-Leishmania activity that is directly linked to their chemical structure.