Unlocking Iridium Chemical Space for Antibiotic Discovery through One-Pot Combinatorial Synthesis in a Direct-to-Biology Approach

Metal-based compounds have emerged as a promising class of antibiotic candidates, demonstrating high hit rates against priority bacterial pathogens without exhibiting increased toxicity compared to purely organic molecules. Here, we report a one-pot, three-component combinatorial strategy for the synthesis of piano-stool Ir(III) cyclopentadienyl Schiff-base complexes as potential antibacterial agents.

Using 15 picolinaldehydes (<b>A</b>–<b>O</b>), 24 amines (<b>1</b>–<b>24</b>), and four Cp/Cp* iridium precursors (<b>Cp1</b>–<b>4</b>), a library of 1440 complexes was generated and screened directly from crude reaction mixtures in a direct-to-biology approach. Biological screening revealed pronounced activity against Gram-positive Staphylococcus aureus, particularly for biphenyl-substituted Cp (<b>Cp2</b>) complexes, while no activity was observed against Gram-negative bacteria.