The (patho)physiological action of copper in humans has been intensively studied, mainly because copper is an endogenous and bioessential element. The copper(I) ion shows an affinity for S-donor groups (such as cysteine or methionine residues in proteins). In contrast, the Copper(II) ion prefers coordination to O- or N-donor groups (oxygen or nitrogen in amino acids), and they participate in a variety of biochemical processes [[1], [2], [3]].

Copper has fascinating roles through interactions with Schiff bases, which have been defined as privileged ligands in organic synthesis, thanks to easy synthesis, good solubility in many solvents, different biological activities, and the ability to form complexes with almost all metals. These complexes are well known for their bioactivities and numerous applications and bioactivities [4]. For example, transition metal complexes with Schiff bases unequivocally show antioxidant [5], anticancer [6], antifungal [7], and antimicrobial [8] activity. The selection of ligands plays a vital role in their bioactive properties, e.g., the Schiff base complexes penetration through the membranes intensifies with its increasing lipophilicity [9,10].

Schiff base complexes have a significant role as chemotherapeutical drugs in medicinal chemistry. For example, it has been proven that different metal-based complexes carrying β-diketones as ligands manifest antiproliferative, apoptotic, or antimetastatic effects in tumor cells in vitro and in vivo [[11], [12], [13]]. A pyrazolone Schiff base Copper(II) complex has been suggested as a potential drug candidate for the treatment of liver cancer because it showed high antiproliferative activity against hepatocellular carcinoma [14].

As an ideal carrier for various therapeutic agents, HSA is a protein of choice for studying drug-protein interaction and its contribution to the distribution and metabolism of the drug through different organs of the human body [15]. For many antitumor agents, the main target in the cell is the hereditary deoxyribonucleic acid (DNA) molecule [16]. Therefore, expanding knowledge of the noncovalent, reversible interaction of the Schiff base type compounds with HSA and DNA gives a better understanding of biochemical processes and manifested biological activities.

In this study, the bio-affinity of six structurally similar tetradentate Schiff base Copper(II) complexes with ethylenediamine in a diamine bridge was investigated through to determination of antioxidant, antifungal, antimicrobial, cytotoxic activities, and binding capacity for major extracellular transport protein, human serum albumin, as well as DNA, by various in vitro and in silico assays.