Cargando…

Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships

Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic anal...

Descripción completa

Detalles Bibliográficos
Autores principales: Machin, Laura, Piontek, Martin, Todhe, Sara, Staniek, Katrin, Monzote, Lianet, Fudickar, Werner, Linker, Torsten, Gille, Lars
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612231/
https://www.ncbi.nlm.nih.gov/pubmed/36296439
http://dx.doi.org/10.3390/molecules27206846
_version_ 1784819723296309248
author Machin, Laura
Piontek, Martin
Todhe, Sara
Staniek, Katrin
Monzote, Lianet
Fudickar, Werner
Linker, Torsten
Gille, Lars
author_facet Machin, Laura
Piontek, Martin
Todhe, Sara
Staniek, Katrin
Monzote, Lianet
Fudickar, Werner
Linker, Torsten
Gille, Lars
author_sort Machin, Laura
collection PubMed
description Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogP(OW) larger than 3.5 and a polar surface area smaller than 100 Å(2). The most effective compounds (IC(50) in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models.
format Online
Article
Text
id pubmed-9612231
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96122312022-10-28 Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships Machin, Laura Piontek, Martin Todhe, Sara Staniek, Katrin Monzote, Lianet Fudickar, Werner Linker, Torsten Gille, Lars Molecules Article Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogP(OW) larger than 3.5 and a polar surface area smaller than 100 Å(2). The most effective compounds (IC(50) in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models. MDPI 2022-10-13 /pmc/articles/PMC9612231/ /pubmed/36296439 http://dx.doi.org/10.3390/molecules27206846 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Machin, Laura
Piontek, Martin
Todhe, Sara
Staniek, Katrin
Monzote, Lianet
Fudickar, Werner
Linker, Torsten
Gille, Lars
Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships
title Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships
title_full Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships
title_fullStr Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships
title_full_unstemmed Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships
title_short Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships
title_sort antileishmanial anthracene endoperoxides: efficacy in vitro, mechanisms and structure-activity relationships
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612231/
https://www.ncbi.nlm.nih.gov/pubmed/36296439
http://dx.doi.org/10.3390/molecules27206846
work_keys_str_mv AT machinlaura antileishmanialanthraceneendoperoxidesefficacyinvitromechanismsandstructureactivityrelationships
AT piontekmartin antileishmanialanthraceneendoperoxidesefficacyinvitromechanismsandstructureactivityrelationships
AT todhesara antileishmanialanthraceneendoperoxidesefficacyinvitromechanismsandstructureactivityrelationships
AT staniekkatrin antileishmanialanthraceneendoperoxidesefficacyinvitromechanismsandstructureactivityrelationships
AT monzotelianet antileishmanialanthraceneendoperoxidesefficacyinvitromechanismsandstructureactivityrelationships
AT fudickarwerner antileishmanialanthraceneendoperoxidesefficacyinvitromechanismsandstructureactivityrelationships
AT linkertorsten antileishmanialanthraceneendoperoxidesefficacyinvitromechanismsandstructureactivityrelationships
AT gillelars antileishmanialanthraceneendoperoxidesefficacyinvitromechanismsandstructureactivityrelationships