Solving the challenging synthesis of highly cytotoxic silver complexes bearing sterically hindered NHC ligands with mechanochemistry

The use of ball-mills enabled the straightforward synthesis of a variety of silver(i) complexes featuring challenging NHC ligands. Sterically hindered including electron-poor or with very low solubility imidazohum salts were ground with silver(i) oxide to furnish heteroleptic or homoleptic complexes in high yields and short reaction times. The synthesis of heteroleptic bis-NHC silver(i) complexes was also performed for the first time in a ball mill. The efficiency and rapidity of the mechanochemical approach enabled the generation of a library of unprecedented NHC silver complexes, whose cytotoxicity on the HCT116 colorectal cancer cell line was evaluated providing a rare example of medicinal mechanochemistry. The cationic silver complexes were found to be more potent than the neutral analogues, with IC50 values down to 21 nM and 256 times more potent than cisplatin.