Find in Library

Leishmaniasis is a vector-borne disease caused by protozoal <i>Leishmania</i> parasites. Previous studies have shown that endoperoxides (EP) can selectively kill <i>Leishmania</i> in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of <i>Leishmania tarentolae</i> promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in <i>Leishmania</i>. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogP_OW larger than 3.5 and a polar surface area smaller than 100 Ų. The most effective compounds (IC₅₀ in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in <i>Leishmania</i>. The identified compound pairs are a good starting point for subsequent experiments in pathogenic <i>Leishmania</i> in vitro and in animal models.