Abstract
Visceral leishmaniasis is a neglected tropical disease with the highest mortality among different forms of leishmaniasis manifestation in humans. The disease is caused by the parasitic protists Leishmania donovani and Leishmania infantum, and treatments remain unsuitable due to high costs, complicated administration, lack of efficacy, variable patient susceptibility, toxic side effects, and rising parasitic resistance. Herein, we report a structure-activity relationship (SAR) exploration of the diacyl-hydrazide scaffold identified to have antiparasitic activity from a high-throughput screen against L. donovani, Trypanosoma cruzi, and Trypanosoma brucei. This SAR study revealed new structural insights into this scaffold related to bioactivity resulting in a new series of lead compounds with nanomolar activity against L. donovani and no toxicity against human THP-1 macrophages. These optimized diacyl-hydrazide compounds set the stage for future drug development and hold promise for a new treatment avenue for visceral leishmaniasis.