2. Academic Validation
  3. O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity

O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity

  • J Med Chem. 2020 Jun 11;63(11):5734-5751. doi: 10.1021/acs.jmedchem.9b02016.
Victoriano Corpas-López 1,  Mavys Tabraue-Chávez 2,  Yudibeth Sixto-López 3,  Sonia Panadero-Fajardo 2,  Fernando Alves de Lima Franco 1,  José F Domínguez-Seglar 2,  Francisco Morillas-Márquez 1,  Francisco Franco-Montalbán 2,  Mónica Díaz-Gavilán 2,  José Correa-Basurto 3,  Julián López-Viota 4,  Margarita López-Viota 4,  José Pérez Del Palacio 5,  Mercedes de la Cruz 5,  Nuria de Pedro 5,  Joaquina Martín-Sánchez 1,  José A Gómez-Vidal 2
Affiliations

Affiliations

  • 1 Departamento de Parasitologı́a, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja, 18071 Granada, Spain.
  • 2 Departamento de Quı́mica Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja, 18071 Granada, Spain.
  • 3 Laboratorio de Diseño y Desarrollo de Nuevos Fármacos y Productos Biotecnológicos, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340 México City, México.
  • 4 Departamento de Farmacia y Tecnologı́a Farmacéutica, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja, 18071 Granada, Spain.
  • 5 Fundación MEDINA, Parque Tecnológico de la Salud, 18016 Granada, Spain.
PMID: 32392053 DOI: 10.1021/acs.jmedchem.9b02016
Abstract

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.

Figures