Promising antileishmanial activity of novel imidazole antifungal drug luliconazole against Leishmania major: In vitro and in silico studies

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 14a-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 mu M) has greater potency than ketoconazole (KET), meglumine antimoniate (MA) and amphotericin B (AmB) (IC50 values of 135, 538 and 2.52 mu M, respectively). Against the amastigote stage, luliconazole at a concentration of 0.07 mu M 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 14 alpha-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. (C) 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.