Bidentate Metal-Binding Motifs in US FDA Approved Small Molecule Drugs

The coordination of metal cations is integral to the mechanism of action of metal-binding pharmaceuticals such as scavengers for chelation therapy and metalloprotein inhibitors. Furthermore, clinically relevant interactions with endogenous metals were initially unrecognized for some drug classes and are still debated in some cases. In this Perspective, we survey the small molecules approved as drugs by the United States Food and Drug Administration (US FDA) looking for structural motifs wherein metal ions could potentially coordinate in a bidentate fashion. We focus on the formation of five- or six-membered chelate rings upon coordination with nitrogen, oxygen and sulfur donors. In addition to well-known metal-binding motifs such as hydroxamic acids, catechols and salicylic acids, our review highlights numerous drugs containing 1,3-dicarbonyl motifs and related oxygen donors. Nitrogen heterocycles are also featured prominently in this survey of bidentate motifs and a clear growth category in recent years.