Metal complexes of silver(I) and copper(II) with Schiff bases derived from mafenide and ethylmafenide: synthesis, characterization, and evaluation of their antibacterial and antitumor activities

Abstract

Bacterial infections constitute a public health case of concern. The high frequency of these diseases is primarily caused by the lack of appropriate treatment of infections or the emergence of multidrug-resistant strains. Meanwhile, the search of alternatives for the treatment of skin tumours is also growing worldwide, as the primary treatment for this disease is surgical resection, which often causes mutilation in patients. An alternative in the search for new molecules with antibacterial and antitumor properties is the synthesis of metallopharmaceuticals. These consists in the combination of a metal ion that has well-established biological actions, such as Cu(II) and Ag(I), with organic ligands, which may or may not have previously established biological activities. One of the first metal complexes discovered (1844) and used was cisplatin, which antitumor activity was confirmed in the 1970s and released for clinical use by the FDA in 1978. Since this discovery, many other ligands have been studied in the synthesis of bioactive complexes, such as sulphonamides, that are currently employed as antifungal and antitumor agents. Recently, our group prepared and evaluated the activities of a new Ag(I) drug candidate containing nimesulide as the ligand, that is a sulphonamide widely used as an anti-inflammatory agent. This complex demonstrated significant antiproliferative activity on skin tumours in in vitro and in vivo studies, as well as antibacterial action on Gram-positive and Gram-negative strains. In this project, two sulphas were selected, mafenide (the active ingredient of the antibacterial drug Sulfamylon®) and ethyl-mafenide (structurally analogous to mafenide) for the synthesis of new Schiff bases that will act as ligands in the synthesis of new Ag(I) and Cu(II) complexes. The obtained complexes will be chemically and spectroscopically characterized and evaluated for their activities against bacterial strains and a panel of tumour cells, with emphasis on squamous cell carcinomas. The interaction of the active complexes with biomolecules, such as DNA and proteins, will be evaluated to assess possible biological targets. Such studies will be conducted using techniques such as agarose and polyacrylamide gel electrophoresis (SDS/PAGE), as well as analysis by UV-Vis electronic spectroscopy and circular dichroism (CD).