Metal-Based Compounds: Relevance for the Biomedical Field

In the field of drug design and the continuous search for new targeted and safe therapeutic options, metal complexes remain one of the most intensely studied classes of compounds, especially as potential antitumor and antibacterial agents [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Transition metal complexes have emerged as powerful candidates at the intersection of medicinal and diagnostic chemistry due to their structural diversity, redox activity, and tunable coordination environments [15,16,17,18,19,20,21].

One of the most compelling advantages of coordination compounds, as compared to organic molecules, lies in their remarkable structural variety. The electronic versatility of transition metals enables them to adopt a variety of oxidation states and endows them with redox activity that is particularly useful in biomedical applications, such as the generation of reactive oxygen species (ROS) [6,22,23,24,25,26,27]. Additionally, these metals exhibit diverse coordination geometries that allow for a specific spatial arrangement of the ligand structures. This geometric flexibility enables the rational design of complexes with tailored reactivity, selectivity, and binding properties toward biological targets like DNA, proteins, and enzymes [11,28,29,30,31]. Moreover, the ligands themselves can possess intrinsic pharmacological activity or bear pharmacophore groups [32,33,34,35,36,37,38], and they can be systematically modified to fine-tune the overall charge, lipophilicity, solubility, and pharmacokinetic behavior of the complex. This modularity allows researchers to design metal-based agents with highly specific biological functions, setting them apart from conventional small-molecule drugs [39,40,41,42] and providing a robust platform for the development of next-generation therapeutics and diagnostics.

The articles collected in this Special Issue stand out thanks to their multidisciplinary approaches, uniting synthesis, crystallography, spectroscopy, and biomolecular interaction studies. They demonstrate rational, target-oriented drug development, harmonizing the precision of coordination chemistry with some of the most urgent demands of modern health challenges: the need for more effective, selective, and safe antitumor and antimicrobial agents.

Psarras and colleagues [43] contribute to this Special Issue with a study on the synthesis, characterization, and potential applications in medicinal chemistry of new Ni(II) complexes containing 3,5–dibromo–salicylaldehyde with 1,10–phenanthroline and neocuproine as co-ligands. The crystal structures revealed distorted octahedral geometries and a unique cis arrangement of coordinating oxygen atoms, a relatively rare occurrence in such systems. The biological studies undertaken show robust interaction of the complexes with biomacromolecules. Their ability to strongly bind and intercalate with calf-thymus DNA was confirmed by UV–vis spectroscopy, viscosity measurements, and ethidium bromide displacement assays. Furthermore, serum albumin binding studies demonstrated that all three complexes bind tightly and reversibly to both human and bovine albumin, suggesting promising pharmacokinetic behavior should these molecules advance toward therapeutic use. The paper brings into focus the dual value of coordination compounds, the intrinsic therapeutic potential of halogenated salicylaldehyde ligands, and the biological relevance of the essential Ni(II) ion in the search for next-generation metal-based drugs.

The article published by Banik et al. [44] reports on the synthesis, characterization, and cytotoxic properties of two new metal–organic multi-component Ni(II) and Co(II) complexes. In both cases, 3-cyanopyridine acts as a ligand, while anthraquinone-1,5-disulfonate and 4-chlorobenzenesulfonate, respectively, play the roles of counter-anionic moieties within their crystal structures. Interestingly, X-ray crystallography, supplemented by theoretical calculations for the Co(II) complex, reveals an unconventional type of Cl^…N “charge reverse” halogen bonding, where the electron acceptor halogen atom is located on the anion—the electron-rich fragment—while the electron donor nitrogen atom is part of the cation—the electron-poor fragment. This rare type of intermolecular bond, as well as the hydrogen bonds and π-stacking interactions, contribute to the stabilization of the supramolecular assemblies. The authors also explore the potential therapeutic implications of the complexes by assessing their antiproliferative activity against Dalton’s lymphoma malignant cancer cell line, with results showing that the compounds are able to induce concentration-dependent cytotoxicity (IC50 43 μM and 78 μM, respectively), with minimal effect on normal healthy peripheral blood mononuclear cells. Furthermore, an in silico molecular docking study was conducted, unveiling the interactions of the compounds with the antiapoptotic BCL protein family involved in cancer cell growth, allowing the authors to propose a mechanism of action for the observed antitumor properties of the complexes.

Enyedy et al. [45] explore the potential of targeted anticancer therapy using hormone-based Cu(II) coordination complexes, with the authors seeking to harness both the receptor-targeting properties of estradiol and the redox reactivity and cytotoxic potential of copper. Therefore, two estradiol derivatives and their metal complexes were synthesized and characterized, and their cytotoxic properties were evaluated. For each ligand, mononuclear Cu(II) complexes were obtained in solution and their redox properties investigated by cyclic voltammetry, as well as their direct reactions with natural reducing agents, glutathione, and ascorbic acid. The biological activity assays revealed that the coordination compounds are somewhat more cytotoxic (IC50 = 15–45 μM) than their corresponding ligands (IC50 = 30–63 μM) and show a better selectivity profile against the MCF-7 human breast and Colo-205 colon adenocarcinoma cell lines. The value of this work resides in coupling selective hormone-based delivery with metal-mediated cell death for the development of next-generation anticancer agents.

Topală et al. [46] report the synthesis, characterization, and anticancer properties of a series of Cu(II) and Ni(II) complexes with a quinoline-derived sulfonamide ligand while revealing a potential mechanism of action, namely DNA interaction and damage by mediating the formation of ROS. Interestingly, the results show that the Ni(II) complex has the highest affinity for nucleic acid in DNA interaction studies, thermal denaturation, and ethidium bromide displacement assays. Two of the Cu(II) compounds were able to cleave DNA in a concentration-dependent manner, while the mechanistic studies indicated that the nuclease activity involved the reduction of Cu(II) to Cu(I) and the formation of hydroxyl radicals and superoxide anions while also suggesting a preference for minor groove binding. The authors also investigated the affinity of the compounds towards bovine serum albumin (BSA) as a model for plasma protein binding, with most of the complexes exhibiting relatively high binding properties. The antitumor activity of the Cu(II) complexes with nucleolytic abilities was tested against the A549 lung cancer cell line, revealing a cytotoxicity that is both dose- and time-dependent (IC50 24.2 μM and 48.2 μM for the two Cu(II) complexes, respectively). The capacity of the compounds to generate intracellular ROS was confirmed with the DCFH-DA assay on the same cancer cell line, showing a dose-dependent activity, significantly higher than that of the positive control. The article brings into focus the potential of coordination compounds for developing new therapeutic agents while also diving deeply into the issue of structure–activity relations.

A comparative study regarding the structure and biological activity of Co(II), Mn(II), Cu(II), Ni(II), and Zn(II) complexes containing a hydrazone-s-triazine ligand is provided by Altowyan and colleagues [47]. Although the compounds bear the same ligand, the different nature of the metal ion and of the co-ligands is reflected in their behavior in the biological environment. The authors report on the synthesis and structural characterization of a new Co(II) complex and focus on its antibacterial and cytotoxic properties, as well as on the comparison of said biological activities of several other coordination compounds with similar structures. The DFT studies reveal that in the case of the Mn(II) and Co(II) complexes, the metal–ligand binding energy was the lowest in the mentioned series, as a consequence of the larger metal ion size and the presence of the strongly coordinating Cl^– co-ligand, while the strongest interaction energy was observed for the Cu(II) complex. The Cu(II) complex proved to be the most effective against the Gram-positive bacterial strains (S. aureus and B. subtilis), while in the case of Gram-negative bacteria, the Co(II) complex was the most active against E. coli, and the Zn(II) complexes displayed the best results against P. vulgaris. The antitumor potential of the compounds was investigated using the HTC-116 colon cancer and A-549 lung cancer cell lines, with the Cu(II) complex showing the highest potency in both cases (27.7 μM and 40.3 μM, respectively). The paper brings into focus the impact of the metal ion’s nature and of the coordination sphere on the therapeutic potential of coordination compounds.

The antibacterial and antifungal activity of a novel germanium coordination compound with 2-amino-3-hydroxybutanoic acid, the essential amino acid threonine, is reported by Kadomtseva and colleagues [48]. The structure of the complex was established through experimental and in silico methods, while the biological studies revealed it possesses significant biocidal properties against several problematic bacterial strains, including S. aureus, E. coli, P. aeruginosa, and C. albicans (MIC: 2.5 μg/mL, 2.5 μg/mL, 2.5 μg/mL, and 10 μg/mL, respectively).

The study published by Tutar and colleagues [49] addresses the pressing issue of antimicrobial resistance, and through their multidisciplinary approach—combining synthesis, structural characterization, in vitro biological assays, and computational modeling—underscores the potential of coordination chemistry in addressing one of modern medicine’s most pressing challenges. The authors synthesized five Ag(I) N-heterocyclic carbene complexes, using benzimidazolium salts with diverse aromatic substitutions. This fine-tuned structural variability allowed the team to probe how subtle electronic and steric differences influence biological activity. Notably, in all cases, the Ag(I) complexes exhibited better activity than the free ligands. One of the complexes bearing an anthracenyl substituent emerged as a frontrunner, demonstrating potent antimicrobial efficacy, with minimum inhibitory concentrations as low as 1.9 µg/mL. The activity of the complexes against S. aureus and C. albicans was comparable to standard therapeutics like ciprofloxacin and fluconazole, respectively. Another strength of the study is its focus on antibiofilm activity, a notoriously difficult frontier in antimicrobial therapy. The ability of the best-performing complex to inhibit E. coli biofilm formation by over 90% at low concentrations is particularly promising. Molecular docking studies revealed a potential mechanism of action for the antimicrobial properties observed, since the most active complex showed high binding affinity towards E. coli DNA gyrase and C. albicans CYP51. The article highlights once more the potential of transition metal coordination compounds as novel therapeutics that can effectively combat drug-resistant pathogens and biofilms.

Pissaro and colleagues [50] focus on the antifungal activity of new Cu(II) binding tertiary N-alkylamine azole derivatives and their potential to combat the antifungal resistance in invasive infectious diseases caused by Candida glabrata. A group of fifteen new azole derivatives were synthesized and characterized, containing either imidazole or 1,2,4-triazole and a series of different metal chelating groups (pyridine, quinoline, 8-hydroxyquinoline, 2-methoxyphenol, and 4-bromophenol), as well as different lengths for the alkyl chain linking the azole to the primary amine in the scaffold. The results showed that the compounds containing the 8-hydroxyquinoline moiety had the highest affinity for the Cu(II) ions, probably due to its bidentate nature. In the absence of Cu(II), the compounds bearing the 8-hydroxyquinoline motif were the most efficient against C. glabrata, with MIC values lower than the reference drug fluconazole (3.125–6.25 μM vs. 104.5 μM). The results were very interesting from a mechanistic point of view, as the antifungal activity was not a consequence of the inhibition of lanosterol 14α-demethylase and ergosterol depletion, but rather a very low intracellular iron concentration, as a result of the azole coordination. For this group of compounds, the addition of Cu(II) led to a pronounced decrease in antifungal activity while remaining more effective than fluconazole. For the majority of the azoles, the antifungal activity increased in the presence of Cu(II). This work highlights the potential of increasing the biological activity of organic compounds through metal ion coordination, thus changing their mechanism of action.

In their contribution to this Special Issue, Varbanov and colleagues [51] present a detailed study regarding the synthesis and structural elucidation of neutral dinuclear tungsten(V) complexes featuring the W₂O₂(μ-O)₂ core. Their work is rooted in the search for novel radiocontrast agents that may overcome the limitations of currently used iodinated compounds. The innovation of this work lies in the successful synthesis of non-ionic, oxo-bridged tungsten complexes coordinated with L-histidine and disubstituted EDTA derivatives. Some of the previous literature has characterized anionic counterparts; however, this is the first report, to the authors’ knowledge, of stable neutral W(V) complexes with these types of ligands. The use of microwave-assisted synthesis is especially noteworthy, offering efficient ligand exchange and suppressing the precursor’s decomposition. While the poor aqueous solubility of the synthesized complexes remains a limiting factor for immediate biomedical translation, this study opens a route for subsequent derivatization, potentially improving pharmacokinetics and biocompatibility.

Unlike the other papers, González-Garibay and colleagues [52] report on the biosynthesis of silver nanoparticles obtained in the presence of a Stenocereus queretaroensis peel extract (SAgNPs) that seem to possess antitumor properties based on a redox mechanism of action resembling the one seen in the case of metal complexes. The article focuses on the evaluation of the SAgNPs’ antiproliferative activity towards MIA PaCa-2 pancreatic epithelial carcinoma cell line, the results showing a concentration-dependent cytotoxicity, with a relatively low IC50 value (15.66 μg/mL). Based on previously published studies, the authors suggest that the anticancer properties of the synthesized SAgNPs may be based on a complex mechanism of action, including their size (an average of 48.8 nm), as well as inducing oxidative stress and DNA damage. Moreover, the authors explored the potential inhibition of the STAT3 protein, which is known to improve matrix metalloproteinase 7 (MMP7) signaling and promote growth and metastasis in pancreatic cancer. The results of the in silico assay reveal a strong interaction with the protein, similar to the selective inhibitor STA21. The paper highlights the potential of metallic nanoparticles as a much-needed alternative or complementary cancer treatment.

As highlighted by the articles in this Special Issue, transition metal complexes are promising candidates for anticancer and antimicrobial therapy thanks to their unique ability to interact with biological systems through mechanisms that often differ from traditional organic drugs. Their metal centers can participate in redox reactions, generating ROS that induce oxidative stress and damage in cancer cells or microbial pathogens. Many metal complexes can also bind to critical biomolecules such as DNA and proteins, disrupting essential cellular functions and triggering apoptosis or inhibiting microbial replication. Moreover, the modular nature of metal complexes allows for the precise tuning of their chemical and physical properties, enabling selective targeting of diseased cells while minimizing harm to healthy tissue. Their potential to overcome drug resistance, particularly in chemotherapy-resistant cancers and antibiotic-resistant pathogens, further strengthens their appeal as next-generation therapeutics.