O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity

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 obser...

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Published inJournal of medicinal chemistry Vol. 63; no. 11; pp. 5734 - 5751
Main Authors Corpas-Lopez, Victoriano, Tabraue-Chavez, Mavys, Sixto-Lopez, Yudibeth, Panadero-Fajardo, Sonia, de Lima Franco, Fernando Alves, Dominguez-Seglar, Jose F., Morillas-Marquez, Francisco, Franco-Montalban, Francisco, Diaz-Gavilan, Monica, Correa-Basurto, Jose, Lopez-Viota, Julian, Lopez-Viota, Margarita, Perez del Palacio, Jose, de la Cruz, Mercedes, de Pedro, Nuria, Martin-Sanchez, Joaquina, Gomez-Vidal, Jose A.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 11.06.2020
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
LEISHMANIA-INFANTUM
HDAC INHIBITORS
IN-VITRO
PROTEIN STRUCTURES
MEGLUMINE ANTIMONIATE
BIOLOGICAL-ACTIVITY
DRUG DEVELOPMENT
HISTONE DEACETYLASE INHIBITORS
BINDING
3-DIMENSIONAL STRUCTURES
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Summary: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.
Bibliography:ObjectType-Article-1
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b02016