High-throughput Triazole-based Combinatorial Click Chemistry for the Synthesis and Identification of Functional Metal Complexes

A new high-throughput combinatorial approach using CuAAc “Click” chemistry has been implemented to make 192 bidentate pyridyl-1,2,3-triazole ligands. This ligand library was coordinated to five metal scaffolds under mild conditions to yield 672 novel metal compounds, representing a novel methodology for the accelerated exploration of the transition metal complex chemical space. The prepared libraries have been showcased for compound discovery primarily in antimicrobial applications, with selected libraries further tested for catalytic and photophysical screening. We demonstrate the versatility of combinatorial metal complex synthesis by screening all crude mixtures for antibacterial activity and cytotoxicity, enabling the rapid identification of hit compounds. Six promising metalloantibiotics have been identified and re-synthesized, exhibiting activity against Gram-positive bacteria in the nanomolar range with favorable therapeutic windows. The reported methodology represents a significant expansion in the field of metal-based combinatorial chemistry and its application towards the systematic coverage of vast chemical spaces in the search for novel molecules with optimized properties.