2. Academic Validation
  3. 2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes

2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes

  • Bioorg Med Chem Lett. 2014 Sep 1;24(17):4151-7. doi: 10.1016/j.bmcl.2014.07.050.
Néstor M Carballeira 1,  Angela Gono Bwalya 2,  Maurice Ayamba Itoe 3,  Adriano D Andricopulo 4,  María Lorena Cordero-Maldonado 5,  Marcel Kaiser 6,  Maria M Mota 3,  Alexander D Crawford 5,  Rafael V C Guido 4,  Deniz Tasdemir 7
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico. Electronic address: nestor.carballeira1@upr.edu.
  • 2 Department of Biological and Pharmaceutical Chemistry, University of London, School of Pharmacy, London WC1N 1AX, UK.
  • 3 Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon 1649-028, Portugal.
  • 4 Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP 13563-120, Brazil.
  • 5 Chemical Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg.
  • 6 Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland.
  • 7 Department of Biological and Pharmaceutical Chemistry, University of London, School of Pharmacy, London WC1N 1AX, UK; School of Chemistry, National University of Ireland, Galway, Ireland. Electronic address: deniz.tasdemir@nuigalway.ie.
PMID: 25103602 DOI: 10.1016/j.bmcl.2014.07.050
Abstract

The malaria parasite Plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (LS) followed by a blood stage with all clinical manifestation of the disease. In this study, we investigated a series of 2-alkynoic fatty acids (2-AFAs) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-Octadecynoic acid (2-ODA) was identified as the best inhibitor of Plasmodium berghei parasites with ten times higher potency (IC50=0.34 μg/ml) than the control drug. In target determination studies, the same compound inhibited three Plasmodium falciparum FAS-II (PfFAS-II) elongation Enzymes PfFabI, PfFabZ, and PfFabG with the lowest IC50 values (0.28-0.80 μg/ml, respectively). Molecular modeling studies provided insights into the molecular aspects underlying the inhibitory activity of this series of 2-AFAs and a likely explanation for the considerably different inhibition potentials. Blood stages of P. falciparum followed a similar trend where 2-ODA emerged as the most active compound, with 20 times less potency. The general toxicity and hepatotoxicity of 2-AFAs were evaluated by in vitro and in vivo methods in mammalian cell lines and zebrafish models, respectively. This study identifies 2-ODA as the most promising antiparasitic 2-AFA, particularly towards P. berghei parasites.

Keywords

2-Octadecynoic acid; Acetylenic fatty acids; Blood stage; Liver stage; Malaria; Plasmodium; Type II fatty acid synthase.

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