Thiosquaramides: dual-function ionophores for Zn ²⁺ and Cl ⁻ with ion dependent anti-microbial activity

Synthetic transmembrane transporters have garnered considerable interest in medicinal chemistry for their ability to modulate cellular processes <i>via</i> ion transport. These ionophores can disrupt intracellular ion homeostasis, often triggering biological responses such as programmed cell death or antimicrobial effects. In this study, we present a series of thionated squaramides that demonstrate dual binding affinity for both metal cations and anionic species, as confirmed by spectroscopic analyses and single-crystal X-ray crystallography. While thiosquaramides have previously been shown to mediate chloride transport across lipid bilayers, we now report their capacity to facilitate Zn²⁺ transport, as assessed using the FluoZin-3 fluorescence assay in a vesicle model. Notably, the ability of these thiosquaramides to act as zinc ionophores correlates with a distinct Zn²⁺-dependent antimicrobial response against <i>Staphylococcus aureus</i>. These findings establish a clear link between zinc transport and biological activity, suggesting that thiosquaramides function through a novel ionophoric mode of action. Collectively, this work introduces a new class of dual-function ionophores with potential as antimicrobial agents and underscores the value of structural diversification in the design of supramolecular therapeutics.