Promising antileishmanial activity of novel imidazole antifungal drug luliconazole against Leishmania major : In vitro and in silico studies
Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Journal of global antimicrobial resistance - 14(2018) vom: 15. Sept., Seite 260-265 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shokri, Azar [VerfasserIn] |
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| Links: |
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| Themen: |
Antileishmanial activity |
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| Anmerkungen: |
Date Completed 23.09.2019 Date Revised 10.12.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jgar.2018.05.007 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM284388149 |
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| 245 | 1 | 0 | |a Promising antileishmanial activity of novel imidazole antifungal drug luliconazole against Leishmania major |b In vitro and in silico studies |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Mirzaei, Hassan |e verfasserin |4 aut | |
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