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

• Published in: Bioorganic & medicinal chemistry letters 2014-09, Vol.24 (17), p.4151-4157
• Main Authors: Carballeira, Néstor M., Bwalya, Angela Gono, Itoe, Maurice Ayamba, Andricopulo, Adriano D., Cordero-Maldonado, María Lorena, Kaiser, Marcel, Mota, Maria M., Crawford, Alexander D., Guido, Rafael V.C., Tasdemir, Deniz
• Format: Article
• Language: English
• Subjects: 2-Octadecynoic acid; Acetylenic fatty acids; Animals; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Blood stage; 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; Liver stage; Malaria; Malaria - drug therapy; Malaria - parasitology; Models, Molecular; Plasmodium; Plasmodium berghei - drug effects; Plasmodium berghei - enzymology; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Structure-Activity Relationship; Type II fatty acid synthase; Zebrafish
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.07.050

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.