Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Leishmaniasis is a significant vector-borne disease caused by Leishmania parasites.
• Endoperoxides (EP) have demonstrated selective killing of Leishmania within host cells.

Purpose of the Study:

• To evaluate the antileishmanial activity and selectivity of novel anthracene-derived endoperoxides (AcEPs) and their analogs.
• To explore the mechanism of action for effective compounds.

Main Methods:

• Synthesis and testing of AcEPs and non-endoperoxidic analogs against Leishmania tarentolae promastigotes (LtP) and J774 macrophages.
• Investigation of compound reactions with iron (II) in chemical systems and within Leishmania.
• Correlation of structural parameters (LogPOW, polar surface area) with antileishmanial activity.

Main Results:

• Pyridyl-/tert-butyl-substituted AcEPs exhibited high efficacy (IC50 < 2 µM) and selectivity (SI > 30).
• Optimal activity was observed for compounds with LogPOW > 3.5 and polar surface area < 100 Å2.
• Endoperoxide activation by iron was confirmed, but molecular structure influenced differential mitochondrial inhibition.

Conclusions:

• Novel AcEPs and their analogs show significant potential as antileishmanial agents.
• Structural features beyond the endoperoxide core are critical for targeted mitochondrial inhibition.
• These findings provide a foundation for developing new treatments against pathogenic Leishmania.