Novel Linezolid analogues with antiparasitic activity against Hymenolepis nana

  • Bioorg Chem. 2020 Dec;105:104359. doi: 10.1016/j.bioorg.2020.104359.
Eleazar Alcántar-Zavala  1 ,  Esteban Hernández-Guevara  2 ,  Adrián Ochoa-Terán  3 ,  Julio Montes-Ávila  4 ,  Edgar A Estrada-Zavala  5 ,  Alex J Salazar-Medina  6 ,  Efraín Alday  7 ,  Alberto Cabrera  1 ,  Gerardo Aguirre  1 ,  Valentín Miranda-Soto  1 ,  Carlos Velazquez  7 ,  Sylvia P Díaz-Camacho  8 ,  José L Medina-Franco  9
Affiliations
  • 1. Centro de Graduados e Investigación en Química, Tecnológico Nacional de México/IT de Tijuana, Tijuana, B.C., Mexico.
  • 2. Facultad de Ciencias Químicas e Ingeniería, Universidad Autónoma de Baja California Campus Tijuana, Tijuana, B.C., Mexico.
  • 3. Centro de Graduados e Investigación en Química, Tecnológico Nacional de México/IT de Tijuana, Tijuana, B.C., Mexico. Electronic address: [email protected].
  • 4. Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sin., Mexico. Electronic address: [email protected].
  • 5. Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sin., Mexico.
  • 6. Cátedras Conacyt - Departamento de Investigación en Polímeros y Materiales, Universidad de Sonora, Hermosillo, Sonora, Mexico.
  • 7. Departamento de Ciencias Químico-Biológicas, Universidad de Sonora, Hermosillo, Sonora, Mexico.
  • 8. Environment and Health Research Unit, Autonomous University of Occident, Los Mochis, Sinaloa, Mexico.
  • 9. Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
PMID: 33096310 DOI: 10.1016/j.bioorg.2020.104359
Abstract

The stereoselective synthesis and anti- Hymenolepis nana activity of six Linezolid-type compounds, obtained by chemical modification of l-Alanine, are reported in this work. The synthetic strategy was to prepare diasteromeric N,N-dibenzylamino oxazolidinones 1 and 2, and coupling with 4-(4-bromophenyl)morpholine (3) to obtain N,N-dibenzylamino Linezolid analogues 4 and 5. A hydrogenolysis reaction over 4 and 5 resulted in amino-free Linezolid analogues 6 and 7, which were acetylated to reach diasteromeric Linezolid analogues 8 and 9. The six Linezolid analogues 4-9 show in vitro antiparasitic activity against Hymenolepis nana cestode, but not against several Bacterial strains. Interestingly, compounds 6, 7 and 9 exhibit high potency, having shorter paralysis and death times after exposure (6-10 and 18-21 min, respectively), shorter than those found with antihelmintic compound Praziquantel (20 and 30 min) at 20 mg/mL. In addition, a cytocompatibility assay of 6-9 with human cells (ARPE-19 cells) demonstrate a non-cytotoxic effect at 0.4 mM. These results show the pharmacological potential of the newly reported Linezolid-type analogues as antiparasitic agents against Hymenolepis nana.

Keywords
Antiparasitic activity; Linezolid analogues; Stereoselective synthesis.
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