Azar Shokri1, Mahdi Abastabar2, Masoud Keighobadi3, Saeed Emami4, Mahdi Fakhar5, Saeed Hosseini Teshnizi6, Koichi Makimura7, Ali Rezaei-Matehkolaei8, Hassan Mirzaei3. 1. Molecular and Cell Biology Research Center, Department of Parasitology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. 2. Invasive Fungi Research Center (IFRC), Department of Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. 3. Pharmaceutical Sciences Research Center, Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. 4. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. 5. Molecular and Cell Biology Research Center, Department of Parasitology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: mahdif53@yahoo.com. 6. Infectious and Tropical Diseases Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. 7. Laboratory of Space and Environmental Medicine, Graduate School of Medicine, Teikyo University, Tokyo, Japan. 8. Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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=0.19μM) has greater potency than ketoconazole (KET), meglumine antimoniate (MA) and amphotericin B (AmB) (IC50 values of 135, 538 and 2.52μM, respectively). Against the amastigote stage, luliconazole at a concentration of 0.07μM 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.
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=0.19μM) has greater potency than ketoconazole (KET), meglumine antimoniate (MA) and amphotericin B (AmB) (IC50 values of 135, 538 and 2.52μM, respectively). Against the amastigote stage, luliconazole at a concentration of 0.07μM 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.