<i>O</i>-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity

Abstract

<i>Leishmania</i> (<i>L.</i>) <i>infantum</i> causes visceral, cutaneous, and mucosal leishmaniasis in humans and canine leishmaniasis in dogs. Herein, we describe that <i>O</i>-alkyl hydroxamate derivatives displayed potent and selective <i>in vitro</i> activity against the amastigote stage of <i>L. infantum</i> while no activity was observed against promastigotes. Compound <b>5</b> showed potent <i>in vivo</i> activity against <i>L. infantum</i>. Moreover, the combination of compound <b>5</b> supported on gold nanoparticles and meglumine antimoniate was also effective <i>in vivo</i> and improved the activity of these compounds compared to that of the individual treatment. Docking studies showed that compound <b>5</b> 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 <b>5</b> represents a new class of selective ligands with antileishmanial activity.