TY - JOUR
T1 - O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity
AU - Corpas-López, Victoriano
AU - Tabraue-Chávez, Mavys
AU - Sixto-López, Yudibeth
AU - Panadero-Fajardo, Sonia
AU - Alves De Lima Franco, Fernando
AU - Domínguez-Seglar, José F.
AU - Morillas-Márquez, Francisco
AU - Franco-Montalbán, Francisco
AU - Díaz-Gavilán, Mónica
AU - Correa-Basurto, José
AU - López-Viota, Julián
AU - López-Viota, Margarita
AU - Pérez Del Palacio, José
AU - De La Cruz, Mercedes
AU - De Pedro, Nuria
AU - Martín-Sánchez, Joaquina
AU - Gómez-Vidal, José A.
N1 - Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/6/11
Y1 - 2020/6/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85086346441&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b02016
DO - 10.1021/acs.jmedchem.9b02016
M3 - Artículo
C2 - 32392053
SN - 0022-2623
VL - 63
SP - 5734
EP - 5751
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -