IONOPHORE PROPERTIES OF MONENSIN DERIVATIVES STUDIED ON HUMAN ERYTHROCYTES BY NA-23 NMR AND K- RELATIONSHIP WITH ANTIMICROBIAL AND ANTIMALARIAL ACTIVITIES( AND H+ POTENTIOMETRY )

Eight derivatives of monensin with a modified C25-C26 moiety were synt hesized. Their ionophore properties were studied on human erythrocytes by measuring Nat influx with Na-23 NMR and concomitant K+ and H+ effl ux by potentiometry. Modification of OH-26 led to inversion of selecti vity 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 mo nensin skeleton was prevented by blocking the terminal OH-25 and -26 f unctions. All the compounds were inactive on Gram-negative bacteria an d fungi. MIC measured on Bacillus cereus showed that derivatives with increased K+/Na+ selectivity were clearly the most active against Baci llus growth. Most of the compounds showed potent antimalarial properti es in the nanomolar range when tested in vitro against Plasmodium falc iparum. The IC(50)s 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 (N a+ and K+) was necessary to investigate the relationship between biolo gical and ionophore properties.