PUBLICATION
2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes
- Authors
- Carballeira, N.M., Bwalya, A.G., Itoe, M.A., Andricopulo, A.D., Cordero-Maldonado, M.L., Kaiser, M., Mota, M.M., Crawford, A.D., Guido, R.V., Tasdemir, D.
- ID
- ZDB-PUB-140812-20
- Date
- 2014
- Source
- Bioorganic & medicinal chemistry letters 24(17): 4151-7 (Journal)
- Registered Authors
- Cordero-Maldonado, Maria Lorena, Crawford, Alexander
- Keywords
- 2-Octadecynoic acid, Acetylenic fatty acids, Blood stage, Liver stage, Malaria, Plasmodium, Type II fatty acid synthase
- MeSH Terms
-
- Animals
- Antimalarials/chemical synthesis
- Antimalarials/chemistry
- Antimalarials/pharmacology*
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Fatty Acid Synthase, Type II/antagonists & inhibitors*
- Fatty Acid Synthase, Type II/metabolism
- Fatty Acids, Unsaturated/chemical synthesis
- Fatty Acids, Unsaturated/chemistry
- Fatty Acids, Unsaturated/pharmacology*
- Humans
- Malaria/drug therapy*
- Malaria/parasitology*
- Models, Molecular
- Plasmodium berghei/drug effects
- Plasmodium berghei/enzymology*
- Plasmodium falciparum/drug effects
- Plasmodium falciparum/enzymology*
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 25103602 Full text @ Bioorg. Med. Chem. Lett.
Citation
Carballeira, N.M., Bwalya, A.G., Itoe, M.A., Andricopulo, A.D., Cordero-Maldonado, M.L., Kaiser, M., Mota, M.M., Crawford, A.D., Guido, R.V., Tasdemir, D. (2014) 2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes. Bioorganic & medicinal chemistry letters. 24(17):4151-7.
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=0.34μg/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 (0.28-0.80μg/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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping