Selective and pH‐Responsive Macrocyclic Anionophores

The ability to selectively control ion transport across membranes is central for identifying synthetic ionophores that can potentially be used as therapeutics for diseases involving dysfunction of natural ion transporters. Herein, a family of C₂-symmetric macrocycles is presented, which is derived from serine or threonine and a disubstituted aromatic moiety. The ion transport behavior of the macrocycles can be precisely tuned by modifying their aromatic core and symmetry. The phenyl-based macrocycles are highly anion-selective and do not disturb vesicular pH gradients, a key step toward safe therapeutic use of ionophores with minimal cytotoxic risk. In contrast, the introduction of pH responsive pyridyl units in the macrocycle results in measurable chloride transport only below pH 5, a feature that can be utilized to target the acidic lysosomal compartments. This work highlights a structure-guided approach to achieving tunable and conditionally active ionophores, with potential implications in biomedical applications.