2026-10-10T14:07:43Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33941021 2026-09-19T00:06:13Z category_4 category_146 category_8 category_12 category_19 category_21 category_272 category_873 category_734 category_133 portal_63 item_type_3 month_year_09_2026

Unlocking Iridium Chemical Space for Antibiotic Discovery through One-Pot Combinatorial Synthesis in a Direct-to-Biology Approach Çağrı Özsan (23184305) Athi Welsh (18298208) Stefano Zineddu (25074185) David R. Husbands (11302778) Kiera Robinson (25074188) Anson Kwok-Hei Chau (25074191) Angelo Frei (1750903) Biochemistry Space Science Microbiology Cell Biology Pharmacology Biotechnology Environmental Sciences not elsewhere classified Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Plant Biology purely organic molecules potential antibacterial agents modular antibacterial platform crude reaction mixtures component combinatorial strategy work establishes ir promising lead compound positive staphylococcus aureus compounds exhibited potent selective antibacterial activity ir15 </ b pot combinatorial synthesis stool ir promising class positive pathogens based compounds screened directly nucleoid morphology negative bacteria moderate cytotoxicity micromolar activity limited hemolysis displayed low cyclopentadienyl schiff biology approach base complexes associated mode antibiotic discovery antibiotic candidates alongside changes 1440 complexes Antibacterial resistance continues to drive the need for exploring novel chemical spaces beyond conventional organic scaffolds. 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. A subset of the compounds exhibited potent and selective antibacterial activity with low mammalian cell toxicity. Dose-response validation identified 4 promising hit candidates, of which <b>Ir15</b> displayed low-micromolar activity against a panel of Gram-positive pathogens, limited hemolysis, and moderate cytotoxicity. Initial mechanistic studies indicate that <b>Ir15</b> acts through a membrane-associated mode of action involving mild membrane depolarization without large pore formation, alongside changes in nucleoid morphology. Overall, this work establishes Ir(III)Cp Schiff-base complexes as a modular antibacterial platform and identifies <b>Ir15</b> as a promising lead compound for further optimization. 2026-09-18T00:00:00Z Dataset Dataset 10.1021/jacsau.6c00813.s003 https://figshare.com/articles/dataset/Unlocking_Iridium_Chemical_Space_for_Antibiotic_Discovery_through_One-Pot_Combinatorial_Synthesis_in_a_Direct-to-Biology_Approach/33941021 CC BY-NC 4.0