Inclusion complex of ketoconazole and p-sulfonic acid calix[6]arene improves antileishmanial activity and selectivity against Leishmania amazonensis and Leishmania infantum

[Display omitted] •The inclusion complex (IC6HKTZ) was confirmed by chemical characterization.•In vitro activity was performed with Leishmania spp promastigotes.•In vitro cytotoxicity of IC6HKTZ on DH82 macrophages was assessed.•PM6HKTZ was not able to increase the leishmanicidal activity when compared with KTZ.•IC6HKTZ showed low toxicity and the lowest IC50 value when compared with free drug. Many previous studies presented the effectiveness of ketoconazole (KTZ) against leishmaniasis. However, the bioavailability and therapeutic efficacy of free KTZ are limited due to its low aqueous solubility. In this study, an inclusion complex (IC6HKTZ) was prepared with p-sulfonic acid calix[6]arene (CX6SO3H) to improve the solubility and efficacy of KTZ against Leishmania amazonensis and Leishmania infantum promastigotes. A linear increase in KTZ solubility as a function of CX6SO3H concentration was verified using the phase-solubility diagram. The resulting diagram was classified as AL-type and a 1:1 host–guest stoichiometry was assumed to prepare IC6HKTZ by freeze-drying. FTIR, TG/DSC, XRD, and solid-state 13C NMR spectroscopy analyses were performed to confirm the formation of IC6HKTZ. The solubility enhancement of KTZ by 120.00 μM CX6SO3H was about 95 times. The IC50 values of IC6HKTZ and free KTZ were 3.95 and 14.35 μM for Leishmania amazonensis and 6.74 and 17.47 μM for Leishmania infantum, respectively. The viability of DH82 macrophages was not affected by CX6SO3H. These results show that CX6SO3H is a new supramolecular carrier system that improves antileishmanial activities to KTZ for the treatment of cutaneous and visceral leishmaniasis.