High-Throughput Synthesis and Screening of Cyclometalated Iridium Complexes for Antibacterial Applications

Abstract

The discovery of novel antibiotics to address the rise of antimicrobial resistance is an increasingly pressing issue for global health. In recent years, transition-metal complexes have gained attention as potential antibacterial agents. We herein describe a new methodology to generate novel cyclometalated iridium compounds with bidentate Schiff ligands in a high-throughput combinatorial approach, alongside the expansion of an existing approach using bidentate pyridine-triazole ligands, with the aim of finding new metalloantibiotics. A total of 552 new complexes were synthesized and evaluated. Variety in the libraries was introduced by including three cyclometalating phenylpyridine ligands, demonstrating that the synthesis can tolerate both electron-rich and electron-poor metal scaffolds while using mild and biologically compatible conditions. Screening of the crude reaction mixtures in a direct-to-biology approach revealed a number of highly active complexes against Gram-positive bacteria, which was confirmed by resynthesis and further testing of lead compounds. This approach widens the scope of metal complex combinatorial chemistry, enabling rapid exploration of the chemical space involving cyclometalated iridium complexes.