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

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.

• Authors: Néstor M Carballeira, Angela Gono Bwalya, Maurice Ayamba Itoe, Adriano D Andricopulo, María Lorena Cordero-Maldonado, Marcel Kaiser, Maria M Mota, Alexander D Crawford, Rafael V C Guido, Deniz Tasdemir
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 17 Pg. 4151-7 (Sep 01 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 25103602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• 2-octadecynoic acid
• Antimalarials
• Fatty Acids, Unsaturated
• Fatty Acid Synthase, Type II

Topics

• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Fatty Acid Synthase, Type II (antagonists & inhibitors, metabolism)
• Fatty Acids, Unsaturated (chemical synthesis, chemistry, pharmacology)
• Humans
• Malaria (drug therapy, parasitology)
• Models, Molecular
• Plasmodium berghei (drug effects, enzymology)
• Plasmodium falciparum (drug effects, enzymology)
• Structure-Activity Relationship
• Zebrafish