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

Vagner T de Queiroz; Bianca de O Botelho; Natália A Guedes; Diana C Cubides-Román; Francisco de P Careta; Jair C C Freitas; Daniel F Cipriano; Adilson V Costa; Ângelo de Fátima; Sergio A Fernandes

doi:10.1016/j.ijpharm.2023.122663

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

Int J Pharm. 2023 Mar 5:634:122663. doi: 10.1016/j.ijpharm.2023.122663. Epub 2023 Feb 2.

Affiliations

¹ Federal University of Espírito Santo (UFES), Graduate Program in Veterinary Sciences (PPGCV), Center of Agricultural Sciences and Engineering (CCAE), Alto Universitário, s/n, 29500-000 Alegre, ES, Brazil; UFES, Graduate Program in Agrochemistry, Center of Exact, Natural and Health Sciences, Alto Universitário, s/n 29500-000 Alegre, ES, Brazil. Electronic address: vagner.queiroz@ufes.br.
² Federal University of Espírito Santo (UFES), Graduate Program in Veterinary Sciences (PPGCV), Center of Agricultural Sciences and Engineering (CCAE), Alto Universitário, s/n, 29500-000 Alegre, ES, Brazil. Electronic address: biancabotelho93@hotmail.com.
³ UFES, Chemistry Department, Center of Exact Sciences, 29075-910 Vitória, ES, Brazil. Electronic address: natalia.guedes@edu.ufes.br.
⁴ UFES, Chemistry Department, Center of Exact Sciences, 29075-910 Vitória, ES, Brazil. Electronic address: dianacubides@yahoo.com.
⁵ UFES, Department of Pharmacy and Nutrition, Center of Exact, Natural and Health Sciences, Alto Universitário, s/n 29500-000, Alegre, ES, Brazil. Electronic address: franciscopcareta@gmail.com.
⁶ UFES, Laboratory of Carbon and Ceramic Materials, Department of Physics, 29075-910 Vitória, ES, Brazil. Electronic address: jairccfreitas@yahoo.com.br.
⁷ UFES, Laboratory of Carbon and Ceramic Materials, Department of Physics, 29075-910 Vitória, ES, Brazil. Electronic address: daniel.cipriano@ufes.br.
⁸ UFES, Graduate Program in Agrochemistry, Center of Exact, Natural and Health Sciences, Alto Universitário, s/n 29500-000 Alegre, ES, Brazil. Electronic address: avcosta@hotmail.com.
⁹ Federal University of Minas Gerais, Department of Chemistry, Institute of Exact Sciences, 31270-901 Belo Horizonte, MG, Brazil. Electronic address: adefatima.geqob@gmail.com.
¹⁰ Federal University of Viçosa, Department of Chemistry, Av. Peter Henry Rolfs, s/n 36570-900 Viçosa, MG, Brazil. Electronic address: santonio@ufv.br.

PMID: 36738805
DOI: 10.1016/j.ijpharm.2023.122663

Abstract

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 A_L-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.

Keywords: Azole compounds; Leishmaniasis; Medicine delivery; Promastigotes; Solid-state NMR spectroscopy; Toxicity to DH82 macrophages.

MeSH terms

Animals
Antiprotozoal Agents* / therapeutic use
Ketoconazole
Leishmania infantum*
Leishmania mexicana*
Macrophages
Mice
Mice, Inbred BALB C

Substances

Ketoconazole
calix(6)arene
Antiprotozoal Agents