O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity

Corpas-López, Victoriano; Tabraue-Chavez, Mavys; Sixto-López, Yudibeth; Panadero-Fajardo, Sonia; Alves de Lima Franco, Fernando; Domínguez Seglar, José Francisco; Morillas Márquez, Francisco; Franco Montalbán, Francisco; Díaz Gavilán, Mónica; Correa-Basurto, José; López-Viota, Julián; López-Viota Gallardo, Margarita; Pérez del Palacio, José; de la Cruz, Mercedes; de Pedro, Nuria; Martín Sánchez, Joaquina; Gómez Vidal, José Antonio

doi:https://doi.org/10.1021/acs.jmedchem.9b02016

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Identificadores

URI: https://hdl.handle.net/10481/107604

DOI: https://doi.org/10.1021/acs.jmedchem.9b02016

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Editorial

American Chemical Society

Materia

Metal nanoparticles

Nanoparticles

Parasites

Peptides and proteins

Redox reactions

Fecha

2020-06-11

Patrocinador

This research was supported by Project P06-CTS-01407 from the Junta de Andalucía (Spain), Project GREIB.PT-2010-10 from the Universidad de Granada (Spain), and Project 20F12/7 from the Universidad de Granada (Spain).

Resumen

Leishmania (L.) infantum causes visceral, cutaneous, and mucosal leishmaniasis in humans and canine leishmaniasis in dogs. Herein, we describe that O-alkyl hydroxamate derivatives displayed potent and selective in vitro activity against the amastigote stage of L. infantum while no activity was observed against promastigotes. Compound 5 showed potent in vivo activity against L. infantum. Moreover, the combination of compound 5 supported on gold nanoparticles and meglumine antimoniate was also effective in vivo and improved the activity of these compounds compared to that of the individual treatment. Docking studies showed that compound 5 did not reach highly conserved pocket C and established interactions with the semiconserved residues V44, A45, R242, and E243 in pocket A of LiSIR2rp1. The surface space determined by these four amino acids is not conserved in human sirtuins. Compound 5 represents a new class of selective ligands with antileishmanial activity.

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