2. Academic Validation
  3. Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery

Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery

  • Eur J Med Chem. 2018 May 25:152:489-514. doi: 10.1016/j.ejmech.2018.04.038.
Miguel Quiliano 1,  Adriana Pabón 2,  Ernest Moles 3,  Leonardo Bonilla-Ramirez 2,  Isabelle Fabing 4,  Kim Y Fong 5,  Diego A Nieto-Aco 1,  David W Wright 5,  Juan C Pizarro 6,  Ariane Vettorazzi 7,  Adela López de Cerain 7,  Eric Deharo 8,  Xavier Fernández-Busquets 3,  Giovanny Garavito 9,  Ignacio Aldana 1,  Silvia Galiano 10
Affiliations

Affiliations

  • 1 Universidad de Navarra, Instituto de Salud Tropical (ISTUN), Campus Universitario, 31008 Pamplona, Spain; Universidad de Navarra, Facultad de Farmacia y Nutrición, Departamento de Química Orgánica y Farmacéutica, Campus Universitario, 31008 Pamplona, Spain.
  • 2 Grupo Malaria, Universidad de Antioquía, Medellín, Colombia.
  • 3 Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, 08028 Barcelona, Spain; Barcelona Institute for Global Health (ISGlobal), Barcelona Center for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, 08036 Barcelona, Spain; Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.
  • 4 Laboratoire de Synthese et Physicochimie de Molécules d'Intéret Biologique SPCMIB-UMR5068, CNRS - Université Paul Sabatier, 118, route de Narbonne, 31062, Toulouse Cedex 09, France.
  • 5 Department of Chemistry, Vanderbilt University, Station B 351822, Nashville, TN 37235, USA.
  • 6 Department of Tropical Medicine, School of Public Health and Tropical Medicine, Tulane University USA; Vector-Borne Infectious Diseases Research Center, Tulane University USA.
  • 7 Universidad de Navarra, Facultad de Farmacia y Nutrición, Department of Pharmacology and Toxicology, Campus Universitario, 31008 Pamplona, Spain.
  • 8 UMR 152 PHARMA-DEV, Université Toulouse, IRD, UPS, 31062, Toulouse, France.
  • 9 Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, Departamento de Farmacia (DFUNC), Grupo de investigación FaMeTra (Farmacología de la Medicina tradicional y popular), Carrera 30 45-03, Bogotá D.C., Colombia.
  • 10 Universidad de Navarra, Instituto de Salud Tropical (ISTUN), Campus Universitario, 31008 Pamplona, Spain; Universidad de Navarra, Facultad de Farmacia y Nutrición, Departamento de Química Orgánica y Farmacéutica, Campus Universitario, 31008 Pamplona, Spain. Electronic address: silvia.galiano@gmail.com.
PMID: 29754074 DOI: 10.1016/j.ejmech.2018.04.038
Abstract

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC50s < 0.28 μM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC50s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds.

Keywords

Antimalarial; Antiplasmodial; Arylamino alcohol; Enantiomer separation; Hsp90; Multi-stage activity.

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