High-throughput triazole-based combinatorial click chemistry for the synthesis and identification of functional metal complexes

Transition metal complexes have found many applications in the modern world ranging from catalysts, luminescent materials to bioactive compounds and more. However, methods for the systematic synthesis and evaluation of large numbers of metal compounds at a time are still limited. Here, a high-throughput combinatorial approach using copper(I)-catalyzed alkyne–azide cycloaddition chemistry is implemented to make 192 bidentate pyridyl-1,2,3-triazole ligands. This ligand library is coordinated to five metal scaffolds under mild conditions to yield 672 metal compounds, allowing for an accelerated exploration of the transition metal complex chemical space. The prepared libraries are showcased for compound discovery in antimicrobial applications through a “Direct-to-Biology” approach, with selected libraries further tested for catalytic and photophysical properties. Six promising metalloantibiotics are identified and re-synthesized, exhibiting activity against Gram-positive bacteria in the nanomolar range with favorable therapeutic windows. Two iridium complexes are selected from a transfer hydrogenation screening assay and re-synthesized, with one showing high catalytic activity. This methodology represents a significant step forward in the field of metal-based combinatorial chemistry and its application towards the systematic coverage of vast chemical spaces in the search for molecules with optimized properties.