Nontoxic Artificial Chloride Channel Formation in Epithelial Cells by Isophthalic Acid‐Based Small Molecules

Artificial channels capable of facilitating the transport of Cl− ions across cell membranes while being nontoxic to the cells are rare. Such synthetic ion channels can mimic the functions of membrane transport proteins and, therefore, have the potential to treat channelopathies by replacing defective ion channels. Here we report isophthalic acid‐based structurally simple molecules 1 a and 2 a, which self‐assemble to render supramolecular nanochannels that allow selective transport of Cl− ions. As evident from the single‐crystal X‐ray diffraction analysis, the self‐assembly is governed by intermolecular hydrogen bonding and π‐π stacking interactions. The MD simulation studies for both 1 a and 2 a confirmed the formation of stable Cl− channel assembly in the lipid membrane and Cl− transport through them. The MQAE assay showed the efficacy of the compounds in delivering Cl− ions into cells, and the MTT assays proved that the compounds are nontoxic to cells even at a concentration of 100 μM. Nontoxic Cl− transport: The work reports two structurally simple isophthalic acid‐based systems that self‐assemble via different intermolecular H‐bonding and π‐π stacking interactions to render artificial channels, which facilitate selective translocation of Cl− ions across liposomes and cells. Interestingly, the transport of Cl− ions by these ion channels across cell membranes do not exert any toxicity, even at elevated concentrations.