English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/188760
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Title

Imidazo[2,1-a]isoindole scaffold as an uncharted structure active on Leishmania donovani

AuthorsArsène, Sobinson; Gómez-Pérez, Veronica; Escarcena, Ricardo; Abengozar, M. A. ; García-Hernández, Raquel; Nácher-Vázquez, Montserrat ; San Feliciano, A.; Gamarro, Francisco; Rivas, Luis ; Del Olmo, E.
KeywordsImidazoisoindolols
Antileishmanial activity
Energy metabolism
Issue Date29-Jul-2019
PublisherElsevier
CitationEur J Med Chem 182:111568 (2019)
AbstractThe human protozoan parasites Leishmania donovani and L. infantum are the causative agents of visceral leishmaniasis, as such, responsible for approximately 30,000 deaths annually. The available chemotherapeutic treatments are reduced to a few drugs whose effectiveness is limited by rising drug resistance/therapeutic failure, and noxious side-effects. Therefore, new therapeutic hits are needed. Compounds displaying the imidazo[2,1-a]isoindole skeleton have shown antichagasic, anti-HIV, antimalarial and anorectic activities. Here, we report the leishmanicidal activity of thirty one imidazo[2,1-a]isoindol-5-ol derivatives on promastigotes and intracellular amastigotes of L. donovani. Eight out of thirty one assayed compounds showed EC50 values ranging between 1 and 2 μM with selectivity indexes from 29 to 69 on infected THP-1 cells. Six compounds were selected for further elucidation of their leishmanicidal mechanism. In this regard, compound 29, the imidazoisoindolol with the highest activity on intracellular amastigotes, induced an early decrease of intracellular ATP levels, as well as mitochondrial depolarization, together with a partial plasma membrane destructuration, as assessed by transmission electron microscopy. Consequently, the inhibition of the energy metabolism of Leishmania plays an important role in the leishmanicidal mechanism of this compound, even when other additional targets cannot be ruled out. In all, the results supported the inclusion of the imidazoisoindole scaffold for the development of new leishmanicidal drugs.
Description35 p.-5 fig.-1 tab.-1 schem.
Publisher version (URL)https://doi.org/10.1016/j.ejmech.2019.111568
URIhttp://hdl.handle.net/10261/188760
DOI10.1016/j.ejmech.2019.111568
ISSN0223-5234
E-ISSN1768-3254
Appears in Collections:(CIB) Artículos
Files in This Item:
File Description SizeFormat 
Eur J Med Chem_ Arsène_manuscrip_2019.docx Embargoed until July 29, 20201,65 MBMicrosoft Word XMLView/Open    Request a copy
Show full item record
Review this work
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.