Beyond silver sulfadiazine: A dive into more than 50 years of research and development on metal complexes of sulfonamides in medicinal inorganic chemistry

Sulfonamides revolutionized the treatment and management of bacterial infections. Prontosil was the very first synthetic antibacterial agent ever used in the clinics and its metabolite, sulfanilamide, led to the development of a diverse range of sulfonamides with a diverse spectrum of action. Although being developed as antibacterial agents, sulfonamides have also shown to present antitumor, antifungal, and antiviral activities. While for antibacterial applications the focus is on the dihydropteroate synthase enzyme, for antitumor compounds a lot of attention has been given to carbonic anhydrases. For antiviral applications some studies focus on inhibiting HIV replication, and with the COVID-19 pandemic in the last years, attention has been given to inhibit SARS-CoV-2 replication as well. For antifungal applications it seems there is a lack of target focus, but with some compounds presenting relevant activities. Silver sulfadiazine was the first metal complex of a sulfonamide to be used in the clinics as a topical agent for prevention and treatment of infections in burn patients and is vastly used to this day. Here, we covered the history of silver sulfadiazine development, its chemical properties, antibacterial activity and clinical data. Controversial results on the true efficacy of silver sulfadiazine as a topical treatment for burn wounds gave rise to ongoing debate on the advantages of using this compound when compared to other dressings loaded or not with silver-containing agents. Nonetheless, the 50-year history of silver sulfadiazine’s successful use in the clinics has motivated the development of other metal complexes of sulfonamides, which are reviewed here. The biological endpoints for these novel metal complexes were not limited to antibacterial use, but expanded to antitumor, antifungal, and antiviral applications as well. Altogether, this review presents the developments in the applications of metal complexes of sulfonamides in medicinal inorganic chemistry in the past years.