The medicinal chemistry of ferrocene and its derivatives

Ferrocene derivatives have attracted significant interest as anticancer, antibacterial, antifungal and antiparasitic drug candidates. Discovered in the 1990s, the two most prominent derivatives, ferroquine and ferrocifen, have since been studied extensively for the treatment of malaria and cancer, respectively. The ferrocenyl moiety in these two compounds participates in important metal-specific modes of action that contribute to the overall therapeutic efficacy of the molecules. Although ferroquine is currently in phase II clinical trials and ferrocifen is in preclinical evaluation, no other ferrocene derivative — in fact, no other non-radioactive organometallic compound of any kind — has advanced into clinical trials. This Perspective delineates strategies for the systematic incorporation of ferrocenyl groups into known drugs or drug candidates, with a view to finding new drug leads. In addition, we provide a critical evaluation of the difficulties associated with obtaining the clinical approval that would enable ferrocene-containing molecules to transition from being synthetic curiosities to effective drugs. The unique properties of ferrocene-containing compounds make them useful for treating many diseases. The most notable drug candidates — the antimalarial ferroquine and the anticancer agent ferrocifen — have been studied for more than two decades but have not yet met clinical approval. This Review describes the design of ferrocene-containing drugs as well as the challenges faced in bringing them into clinical use.