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 P. 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 P. 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.

Discovery of Marinoquinolines as Potent and Fast-Acting Plasmodium falciparum Inhibitors with in Vivo Activity

“…Subsequently, the SAR of the 4-phenyl substituent was explored, as shown in Table 2. Various substituents, such as 4-OMe (9), 3,5-OMe (10), 3,4,5-OMe (11), Cl (12), Br (13), NO 2 (14), NH 2 (15), NMe 2 (16), COOH (17), and COOMe (18), were tolerated at the 4-phenyl substituent of the marinoquinoline; however, none of them improved potency. On the other hand, compound 16, a dimethylaniline derivative, showed a significant improvement in the selectivity index (SI > 104).…”

“…The human malaria parasite has a complex life cycle that includes several developmental stages in the human host and the mosquito vector, which tremendously contributes to the challenge of eradicating malaria. − Disease control still relies on chemotherapy; however, drug resistance is a limiting factor, and the emergence of artemisinin resistance in southeast Asia and China is a serious threat to the global control of P. falciparum malaria. − Therefore, the discovery and development of new and efficacious drugs for the treatment and prevention of malaria are urgently needed to both overcome resistance and meet the challenge of eradicating malaria. − Due to the limitations of available chemotherapies, several efforts have focused on expanding the range of new antimalarial compounds to thwart parasite growth. − In this context, ideal new drugs should (1) not exhibit cross-resistance to existing drugs, (2) be administered as a single dose, (3) prevent transmission (active against the sexual stages of the parasite), and (4) provide chemoprotection (active against liver stages) …”

Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria

“…The 2-alkynoic fatty acids inhibit the so-called type II fatty acid synthase (FASII), an exclusive eight-enzyme complex involved in fatty acids synthesis in plasmodium parasites. Also, 2-ODA (53) and 2-HDA (54) showed good inhibition of three enzymes of the complex (IC 50 1-2 µM) by binding to a different site from that of the substrate or the cofactor [327].…”

Mediterranean Diet: Lipids, Inflammation, and Malaria Infection

“…Treatment with 2-ODA and 2-TDA was effective in treating infection and killing parasites in hepatic cell cultures. Among them, 2-ODA was the most effective inhibitor, with the three critical enzymes in the FAS II elongation pathway being even more potent than primaquine [ 144 ].…”