A growing interest in the development of novel metallodrugs arose over the last decades, as a consequence of the emerging threat of anticancer and antibiotic drug resistance. Among complexes of other transition metals, those of Group 11 metals display promising properties for successfully combating life-threatening diseases [1,2]. The therapeutic potency of this class of complexes derives from the unique chemical character of their univalent d10 metal ions, which induce modes of bioactivity not usually observed in commonly used drugs, such as the platinum-based drugs used in cancer therapy [3,4]. In addition, the bioactive efficacy of these complexes can be enhanced by appropriate ligands. Frequently, heteroleptic complexes bearing two or three different types of ligands have been utilized, aiming to combine their individual bioactivity effects [5]. Generally, ligands play key roles in the structural and physicochemical properties of their complexes which, in turn, have profound effects on their biological activity. In particular, they determine the coordinative saturation of the metal ions and, therefore, the reactivity of their complexes with biomolecules. Furthermore, they control their kinetic stability and bioavailability, as well as their lipophilicity and affinity towards specific biological substrates, which are related to the in vivo instability and cell selectivity of the complexes, properties that are of critical importance in the design of effective metal-based chemotherapeutic agents.

A class of ligands that has been extensively used for the synthesis of Group 11 metal complexes for medicinal chemistry applications includes phosphines (PR3) and diphosphines (P^P) [[6], [7], [8]]. The favorable soft Lewis-acid/base interactions of these P-donor ligands with the closed-shell d10 metal ions, in combination with suitable R substituents, can enhance the kinetic stability of their complexes, contributing substantially to the controlled release of the metal ions at their target sites [9]. In addition, the choice of R substituents with appropriate lipophilic character offers the ability to finely tune the hydrophilicity/lipophilicity balance and, therefore, the pharmacokinetic stability of their complexes [10,11]. Moreover, their inherent physicochemical characteristics are key determinants of the bioactivity mechanisms of their complexes. Specifically, there have been reports on the ability of phosphines to target and disrupt the mitochondria respiratory chain, [12,13] while they sometimes lead to selective antiproliferative activity towards cancer over normal cells [6,14]. For example, [Cu(dppe)2Cl] and [Cu(dppey)2Cl], where dppe = 1,2- bis(diphenylphosphino)ethane and dppey = 1,2-bis(di-2-pyridylphosphino)ethane, have been found to exhibit significant in vitro cytotoxic activity against different tumor mice models in a non-selective manner over normal cells, whereas the less liphophilic [Ag(d3pype)2]NO3, where d3pype = 1,2-bis(di-3-pyridylphosphino)ethane, exerted strong in vitro cytotoxic effect against carcinoma cells and low toxicity against healthy cells [15,16]. Finally, a number of Group 11 metal complexes with phosphine ligands that exhibit excellent in vitro antibacterial activity have also been reported [17,18].

Another class of ligands that is also attracting great attention for the development of bioactive Group 11 metal complexes comprises N-heterocyclic carbenes (NHCs) [[19], [20], [21], [22], [23]]. Given their strong 2-electron σ donor character, these C-donor ligands coordinate to metal ions forming complexes which can be stable in air, water, acids, or heat [[24], [25], [26]]. Furthermore, they offer the possibility of easy structural modification at the N,N΄-positions of their heterocyclic core with groups of diverse electronic and/or steric properties, as well as varying lipophilicity [27]. Moreover, the introduction of suitable functional groups at these positions may allow the bio-orthogonal conjugation of their complexes with biomolecules to reduce their off-target bioactivity [28]. Among Group 11 metal complexes with NHC ligands, those of Au(I) dominate the field of anticancer research [29,30], while their Cu(I) and Ag(I) counterparts have much less been investigated. However, considering that essential metal ions, generally, have lower chances for developing harmful effects on human normal cells, NHC-Cu(I) complexes appear to be excellent candidates as potential therapeutic agents. In fact, a number of such complexes has already been reported to display higher in vitro cytotoxicity than cisplatin against certain types of cancer cells. For example, [CuCl(NHC)] complexes, where NHC = 1,3-dimesityl-imidazol-4,5-dihydro-2-ylidene, 1,3-dimesityl-2,3-dihydro-1H-imidazole, exhibited 80-to-140 times lower IC50 values compared to cisplatin against MCF7 cancer cells [31]. NHC-Ag(I) complexes have also been investigated for their in vitro anticancer potential, showing encouraging results. In a number of cases, while exhibiting IC50 values lower than cisplatin, they also display biocompatibility against normal cells [[32], [33], [34], [35], [36]]. Noteworthy, the photoluminescence properties of some cytotoxically active NHC-Ag(I) complexes have been utilized for monitoring their biodistribution in cancer cells, allowing to shed light on their bioactivity mechanisms [37,38]. Finally, several Cu(I) and Ag(I) complexes with NHC ligands have been reported to exhibit excellent bactericidal or bacteriostatic behavior [[39], [40], [41]].

Herein, we present a series of mononuclear thioamidato Ag(I) and Cu(I) complexes bearing either a diphosphine or a NHC as auxiliary ligands, and the study of their in vitro bioactivity against a series of bacterial and cancer cells. Heterocyclic thioamides constitute a diverse class of compounds with important role in drug discovery [42]. Their structural relevance with components of important biomolecules and their inherent bioactivity [42,43], in combination with their versatile coordinating properties, have resulted in complexes with diverse structural characteristics and, frequently, high bioactivity [5,[44], [45], [46], [47]]. Correlations of the results of our bioactivity studies with the individual characteristics of the complexes revealed the great importance of the identity of the co-ligand, as well as the metal ion, for achieving high bioactivity, while they also open the way towards the discovery of novel potent and dual metallo-therapeutic agents. Aiming to shed light on the mechanism of the anticancer activity of the most highly active complex, flow cytometry analysis was conducted revealing that cell death occurs through an apoptotic pathway, while molecular docking calculations provided insights in the mechanism of apoptosis.