Differential in vitro activities of ionophore compounds against Plasmodium falciparum and mammalian cells

Abstract

Twenty-two ionophore compounds were screened for their antimalarial activities. They consisted of true ionophores (mobile carriers) and channel-forming quasi-ionophores with different ionic specificities. Eleven of the compounds were found to be extremely efficient inhibitors of Plasmodium falciparum growth in vitro, with 50% inhibitory concentrations of less than 10 ng/ml. Gramicidin D was the most active compound tested, with 50% inhibitory concentration of 0.035 ng/ml. Compounds with identical ionic specificities generally had similar levels of antimalarial activity, and ionophores specific to monovalent cations were the most active. Compounds were further tested to determine their in vitro toxicities against mammalian lymphoblast and macrophage cell lines. Nine of the 22 compounds, i.e., alborixin, lonomycin, nigericin, narasin, monensin and its methylated derivative, lasalocid and its bromo derivative, and gramicidin D, most specific to monovalent cations, were at least 35-fold more active in vitro against P. falciparum than against the two other mammalian cell lines. The enhanced ability to penetrate the erythrocyte membrane after infection could be a factor that determines ionophore selectivity for infected erythrocytes.

The inhibitory effects of H+K+ATPase inhibitors on human neutrophils in vitro: Restoration by a K+ ionophore

“…Due to their lipophilicities, these compounds are incorporated into natural or artificial membranes and facilitate the diffusion of ions, leading to ionic gradient and content modifications [26]. Nigericin is considered a true carboxylic ionophore because it acts as a mobile carrier and possesses a high selectivity for potassium ions [27]. In our study, nigericin itself affected neither spontaneous migration nor fMLP-induced chemotaxis, which is in agreement with a previous report showing that nigericin does not inhibit chemotaxis in the presence of potassium [28].…”

Channels and transporters as drug targets in the Plasmodium-infected erythrocyte

“…An alternative approach to increasing the Na + permeability of the parasitised erythrocyte membrane could involve the use of Na + ionophores. Such compounds have been shown previously to kill parasites in culture (Gumila et al, 1996) as well as to induce haemolysis of infected cells at concentrations at which uninfected cells remain stable (Otten-Kuipers et al, 1997).…”

Preparation and Characterization of Monensin Loaded PLGA Nanoparticles: <I>In Vitro</I> Anti-Malarial Activity Against Plasmodium Falciparum

“…Its synthetic and semi synthetic derivatives are reported to have antimalarial activities that are executed by disruption of ionic gradients in the malaria parasite. [9][10][11][12] In recent reports by Mahmoudi et al 13 and Leitao et al 14 monensin has been shown active against the hepatocytic stages of malaria parasites. 13 14 Despite its strong potential as an antimalarial its extreme hydrophobic nature hinders its application in therapy.…”