Ionophore Properties of Monensin Derivatives Studied on Human Erythrocytes by 23Na NMR and K+ and H+ Potentiometry: Relationship with Antimicrobial and Antimalarial Activities

Abstract

Eight derivatives of monensin with a modified C25−C26 moiety were synthesized. Their ionophore properties were studied on human erythrocytes by measuring Na⁺ influx with ²³Na NMR and concomitant K⁺ and H⁺ efflux by potentiometry. Modification of OH-26 led to inversion of selectivity of transport in favor of K⁺/Na⁺ in comparison with monensin. This selectivity disappeared by suppression of the C26-OH moiety. Finally the ionophore ability was lost if the head-to-tail chelation of the monensin skeleton was prevented by blocking the terminal OH-25 and -26 functions. All the compounds were inactive on Gram-negative bacteria and fungi. MIC measured on Bacillus cereus showed that derivatives with increased K⁺/Na⁺ selectivity were clearly the most active against Bacillus growth. Most of the compounds showed potent antimalarial properties in the nanomolar range when tested in vitro against Plasmodium falciparum. The IC₅₀s measured were correlated with the whole Na⁺ and K⁺ transport efficiency rather than with the ionic selectivity. In both cases determination of initial fluxes of transport for both cations (Na⁺ and K⁺) was necessary to investigate the relationship between biological and ionophore properties.