Objective: Leishmaniasis is a vector-borne infection caused by the protozoan parasite Leishmania. In recent years, the emergence of resistant Leishmania species to antileishmanial drugs has highlighted the need for new antileishmanial molecules. This study aimed to investigate the potential of mangostin derivatives as an alternative drug candidate for leishmaniasis and the effectiveness of its combination with antileishmanial drugs.

Methods: The pure and analytical forms of α/ɣ-mangostin used in this study. The cytotoxic activity of α/ɣmangostin was assessed against L929 fibroblasts, and their antileishmanial activity was evaluated against the Leishmania tropica strain using the broth microdilution method. The combination of mangostin derivatives with the antileishmanial drugs pentostam and miltefosine was determined using the checkerboard assay.

Results: The cytotoxic activity of α- and ɣ-mangostin against fibroblasts ranged from 10.15 to 12.77 μM and 15.99 to 25.57 μM at 24, 48, and 72 hours, respectively. Their antileishmanial activities during the same time intervals ranged from 25.85 to 38.54 μg/mL for α-mangostin and from 45.51 to 80.99 μM for ɣ-mangostin. Both xanthones exhibited potent antileishmanial activity but showed low selectivity (SI<1). Evaluation of the combination effects revealed synergistic interactions between α-mangostin and both pentostam and miltefosine after 48 hours. In contrast, synergisti

Conclusion: Our findings demonstrate that the xanthones, despite their strong antileishmanial activity, exhibit low selectivity. However, their combination with pentostam and miltefosine resulted in synergistic interactions. These results suggest that the investigated xanthones could serve as promising candidates for the development of novel antileishmanial drugs.