Rational Design of Silicon‐Based Zinc Ionophores

Ionophores transport ions across biological membranes and have wide‐ranging applications, but a platform for their rapid development does not exist. We report a platform for developing ionophores from metal‐ion chelators, which are readily available with wide‐ranging affinities and specificities, and structural data that can aid rational design. Specifically, we fine‐tuned the binding affinity and lipophilicity of a ZnII‐chelating ligand by introducing silyl groups proximal to the ZnII‐binding pocket, which generated ionophores that performed better than most of the currently known ZnII ionophores. Furthermore, these silicon‐based ionophores were specific for ZnII over other metals and exhibited better antibacterial activity and less toxicity to mammalian cells than several known ZnII ionophores, including pyrithione. These studies establish rational design principles for the rapid development of potent and specific ionophores and a new class of antibacterial agents. A general approach to rationally design ZnII ionophores from ZnII chelator by incorporation of silyl‐based groups is reported. These ionophores were more potent than several reported ZnII ionophores. Furthermore, these ZnII ionophores demonstrated selective antibacterial activity and lower mammalian cell toxicity compared to the known ionophore, pyrithione.