Promising antileishmanial activity of novel imidazole antifungal drug luliconazole against Leishmania major: In vitro and in silico studies. (September 2018) - Shokri, Azar
Graphical abstract: Highlights: In vitro activity of the novel imidazole antifungal drug luliconazole against Leishmania major was investigated. Luliconazole at 0.07 μM decreased the number of amastigotes significantly more than ketoconazole and meglumine antimoniate. Docking study revealed that luliconazole can properly interact with the target enzyme in Leishmania. The drug–enzyme interaction is mainly via co-ordination with heme and multiple hydrophobic interactions. Potent efficacy of luliconazole at low concentrations on L. major makes it a good candidate for treatment of leishmaniasis. Abstract: Objectives: Pentavalent antimonials have been used for the treatment of leishmaniasis for over 70 years, however they are limited by their toxicity. Unfortunately, the efficacy of first-line drugs for the treatment of leishmaniasis has decreased and resistance is noticeable. Luliconazole is a new azole with unique effects on fungi that has not yet been tested on Leishmania parasites. Methods: In this study, the cytotoxicity and antileishmanial activity of luliconazole were evaluated in vitro against promastigotes and intracellular amastigotes of Leishmania major . The docking simulation with the target enzyme, sterol 14α-demethylase (CYP51) was performed using AutoDock 4.2 program. Results: The IC50 (concentration of test compound required for 50% inhibition) against promastigotes revealed that luliconazole (IC50 = 0.19 μM) has greater potency than ketoconazole (KET), meglumine antimoniate (MA) and amphotericin B (AmB) (IC50 values of 135, 538 and 2.52 μM, respectively). Against the amastigote stage, luliconazole at a concentration of 0.07 μM decreased the mean infection rate and the mean number of amastigotes per macrophage more effectively than MA ( P < 0.004) and KET ( P < 0.043), but there was no difference compared with AmB ( P > 0.05). A docking study of luliconazole with the cytochrome P450 enzyme sterol 14α-demethylase (CYP51) revealed that this azole drug can properly interact with the target enzyme in Leishmania mainly via coordination with heme and multiple hydrophobic interactions. Conclusion: These results show the potent activity of luliconazole at extremely low concentrations against L. major . It may therefore be considered as a new candidate for treatment of leishmaniasis in the near future.