Structure-activity relationships among noncyclic dicarboxamide Li⁺-selective carriers studied in lipid bilayer membranes

The structure-activity relationships among three noncyclic diimide ionophores, designed to be Li⁺ carriers, were studied in lipid bilayer membranes. These ionophores (ETH1644, ETH1810, and ETH1811) vary in their N-imide substituents, going from two isobutyls to one isobutyl and one cyclohexyl to two cyclohexyls, respectively. ETH1811 was found to form two types of complexes with 1:1 and 1:2 ion-carrier stoichiometries, the former type dominant over most of the ionophore (0.1-10 μm) and salt (0.01 - 1.0 m) concentration ranges studied. In contrast, ETH1644 and ETH1810 were previously found to form a single type of complex with the 1:2 stoichiometry. The alkali cations selectivity sequence induced by ETH1811 is Li⁺ (1) > Na⁺ (0.08) > K⁺ (0.02) > Cs⁺ (0.008). These ETH1811-induced ionic selectivites as well as its relative potency in ion transport were found to be inferior to those of ETH1644 and of ETH1810 (the latter being the best in this series). The conductance-voltage relationships reported here, for all three ionophores transporting alkali cations, were found to fit with a transport mechanism in which the diffusion of the ion-ionophore complex across the membrane is the single rate-limiting step, with the following exceptions: The addition of the dissociation of the ion-carrier complex as a second rate limiting step, for the Li⁺-ETH1810 and the Li⁺-ETH1811 systems. For ETH1810 the kinetics of the dissociation step is a minor, whereas for ETH1811 case it is a significant, addition (the ratio of the diffusion to dissociation rate constants being 0.08 and 0.2, respectively). The implications of the effects of the continuous structural change of these ionophores on their performance as ion carriers and on the design and synthesis of improved Li⁺-selective ionophores are discussed.