A Recent Review of the Therapeutic Potential of Gold, Platinum, and Puthenium Complexes Combined with Certain Organic Compounds

Abstract

The synthesis and systematic investigation of inorganic and organic compounds are fundamental to medicinal and pharmaceutical chemistry, particularly for developing novel therapeutic agents. Transition-metal complexes and bioactive organic compounds have shown significant potential to modulate cellular pathways, yielding anticancer, antimicrobial, and anti-inflammatory effects. This review summarizes recent advances in the synthesis, structural characterization, and therapeutic evaluation of gold (Au), platinum (Pt), and ruthenium (Ru) complexes, as well as selected organic compounds, with an emphasis on their biological activities and potential clinical relevance. The integration of synthetic chemistry with biological evaluation underscores the therapeutic potential of gold (Au), platinum (Pt), and ruthenium (Ru) complexes, as well as organic compounds. Au(I/III), Pt(II/IV), and Ru(II/III) complexes demonstrated notable in vivo anticancer activity, while selected organic derivatives exhibited promising bioactive properties. This review aims to support researchers and clinicians in the ongoing development of novel compounds with clinical relevance for anticancer, antimicrobial, and anti-inflammatory applications.

1. Introduction

Over recent decades, the merging of coordination chemistry and medicinal chemistry has expanded the possibilities for creating metal-based therapeutics. Among transition metals, gold (Au), platinum (Pt), and ruthenium (Ru) have attracted significant attention because of their unique physicochemical characteristics, flexible coordination geometries, and notable biological activities. These metals can form complexes with various organic ligands, producing compounds showing promising anticancer, antimicrobial, anti-inflammatory, and diagnostic properties. The clinical success of platinum-based drugs such as cisplatin [1], carboplatin [2,3,4,5,6,7,8,9], and oxaliplatin [10,11,12,13,14] has provided a solid foundation for exploring other metal complexes with greater selectivity and lower toxicity (see Figure 1).

Pt(IV) complexes constitute an emerging class of platinum-based therapeutics aimed at mitigating adverse effects, increasing efficacy, and overcoming resistance [15]. Figure 2 depicts the chemical structures of Pt(IV) complexes presently utilized in clinical settings. Recent research efforts have focused on modifying cisplatin, oxaliplatin, and other Pt(II) complexes to synthesize novel Pt(IV) compounds bearing alternative axial ligands.

Despite limited improvements in overall survival, research continues to focus on Pt(IV) complexes as next-generation platinum anticancer agents. Their octahedral six-coordinate structure provides greater kinetic stability than Pt(II) drugs, reducing premature interactions with biomolecules and allowing the attachment of axial ligands for targeted delivery or combination therapy [16]. This enhanced stability minimizes deactivation and systemic toxicity while enabling intracellular activation through reduction to the active Pt(II) form [17].

Since the recognition of compounds such as cis-[PtCl₄(NH₃)₂] as anticancer agents, Pt(IV) complexes have attracted considerable interest because of their favorable synthesis and delivery properties [1,18]. Their kinetic inertness decreases unwanted biological interactions [19], while efficient cellular uptake and enzymatic reduction by biological reductants are essential for activating their antitumor effects [20,21]. These characteristics make Pt(IV) prodrugs promising candidates for overcoming drug resistance and improving treatment selectivity [22]. In avascular tumors, which lack functional blood vessels and experience severe hypoxia, conventional therapies are often ineffective due to oxygen dependence and poor tissue penetration. Pt(IV) complexes show particular promise in these environments because hypoxic reducing conditions activate the Pt(IV) prodrug into its highly cytotoxic Pt(II) form. This selective activation enhances stability during circulation while concentrating activity at the tumor site, making Pt(IV) compounds attractive for treating aggressive, therapy-resistant cancers [23]. Their octahedral structure also allows modification of axial ligands, improving tumor selectivity, cellular uptake, and biocompatibility [24].

Interest in Pt(IV)-based anticancer agents has grown significantly, and many newly synthesized platinum compounds now belong to this class. Their effectiveness stems from the ability to modify both axial and equatorial ligands, enabling a prodrug strategy in which relatively inert Pt(IV) species are reduced intracellularly by agents such as glutathione or ascorbic acid. Reduction releases the axial ligands and generates active Pt(II) species that bind DNA and inhibit tumor growth. Studies have shown that some trans-platinum complexes possess cytotoxicity comparable to cisplatin, prompting a reassessment of structure–activity relationships (SAR). The nature of the leaving group strongly influences toxicity and efficacy, while mixed ammine/amine complexes often display lower toxicity with maintained or enhanced anticancer activity. Recent developments include Pt(IV) prodrugs and terpyridine-modified complexes designed to improve selectivity and reduce side effects. Platinum drugs such as cisplatin exert their anticancer effects primarily through DNA damage and reactive oxygen species (ROS) generation.

Advances in metal-based therapeutics have also highlighted the potential of gold-based systems. Functionalized gold nanoparticles (AuNPs) serve as theranostic platforms that combine imaging and targeted therapy. Surface ligands enable tumor-specific accumulation through the Enhanced Permeability and Retention (EPR) effect and receptor-mediated endocytosis, improving drug delivery to cancer tissues.

Gold complexes, particularly Au(I) and Au(III), differ from platinum drugs by primarily targeting cellular redox balance rather than DNA. They inhibit thioredoxin reductase (TrxR), a key antioxidant enzyme overexpressed in many cancers. Binding to active-site selenocysteine residues disables the thioredoxin system, leading to ROS accumulation, mitochondrial dysfunction, and apoptosis. AuNPs similarly promote oxidative stress, DNA damage, and mitochondrial impairment. Gold compounds, including the clinically used Au(I) drug auranofin, exploit the dependence of cancer cells on TrxR-mediated redox homeostasis. By irreversibly inhibiting TrxR, they induce lethal oxidative stress and represent promising candidates for treating tumors resistant to conventional chemotherapy. Beyond gold and platinum, ruthenium (Ru) complexes have become an important and versatile group of metallodrugs. Often viewed as top alternatives to traditional platinum-based treatments, ruthenium compounds provide several unique therapeutic benefits. Unlike cisplatin, a platinum-based drug, NAMI-A affects metastasis [25]. Whereas platinum compounds can be highly cytotoxic, NAMI-A is much less so [26]. Figure 3 shows the chemical structures of ruthenium compounds with biological activities.

Unlike cisplatin’s DNA-centric focus, ruthenium complexes can target a broader array of biological components, including specific proteins and enzymes involved in metastasis. Their superior water solubility facilitates easier formulation and more efficient transport in the bloodstream. Many Ru(III) complexes act as prodrugs, remaining relatively inactive until they reach the “reducing” and slightly acidic tumor microenvironment, where they are converted to the more reactive Ru(II) species.

By integrating the redox-disrupting capabilities of gold with the selective activation of ruthenium, researchers are developing a more nuanced, multi-targeted approach to modern oncology.

The biological activity of metal-based anticancer complexes is strongly influenced by the nature of their coordinated ligands. Ligands determine the stability, lipophilicity, cellular uptake, target selectivity, and pharmacokinetic behavior of the complexes. In general, N-heterocyclic carbene (NHC), phosphine, and polydentate nitrogen-donor ligands have demonstrated superior performance because they provide high kinetic stability and facilitate efficient interactions with biological targets. For gold complexes, NHC ligands often exhibit enhanced stability and potent inhibition of thioredoxin reductase compared with phosphine-based analogues. In platinum complexes, amine ligands improve DNA binding properties and contribute to greater therapeutic efficacy, whereas bulky or sterically demanding ligands may reduce off-target toxicity and help overcome drug resistance. Ruthenium complexes containing polypyridyl, arene, or other chelating ligands generally display improved stability, favorable redox properties, and enhanced tumor selectivity. Overall, ligands that combine high complex stability with selective targeting and favorable pharmacokinetic properties tend to exhibit superior anticancer performance, emphasizing the importance of rational ligand design in the development of next-generation metal-based therapeutics.

Besides metal-based agents, organic compounds also play essential roles in targeting biological systems, acting as therapeutic agents and ligands that enhance the pharmacological properties of metal centers. This narrative review provides a detailed overview of recent advancements in synthesis methods, structural analysis, and the therapeutic uses of gold, platinum, and ruthenium complexes. It offers an updated, focused, and thorough view on the synthesis and characterization of inorganic compounds with biological effects, especially in antitumor and antibacterial activities. Unlike earlier reviews, this work covers metal complexes with potential therapeutic benefits with anticancer and antibacterial properties. By combining these perspectives, the review aims to serve as a resource for researchers and professionals in clinical, medical, and health-related fields. Most review articles in the literature focus on the synthesis, biological activity, and mechanism of action of only one of the metals under consideration, without comparing which of them are more suitable for further research efforts.

To improve the technical framework of this review, the discussed compounds are evaluated according to several key parameters that influence their therapeutic relevance: metal oxidation state, coordination geometry, ligand environment, redox behavior, mechanism of action, cytotoxicity or antimicrobial profile, selectivity toward pathological versus healthy cells and in vivo validation.

2. Biological and Medicinal Application of Metal Complexes

2.1. Inorganic Compounds with Anti-Cancer Properties

2.1.1. Gold(I/III)-Based Anti-Cancer Compounds

Gold compounds, mainly in Au(I) and Au(III) oxidation states, have long been studied for their medicinal properties, including anticancer, anti-inflammatory, and antirheumatic effects [27,28]. Their activity extends beyond DNA binding, involving apoptosis induction, DNA damage, and inhibition of angiogenesis. Ligand systems such as carbenes, phosphines, porphyrins, and dithiocarbamates enhance their pharmacological versatility and stability.

Gold nanoparticles further improve therapeutic efficiency by enabling targeted delivery to tumors and reducing toxicity to healthy tissues. In particular, Au(I) N-heterocyclic carbene complexes offer high stability due to strong metal–carbon bonds, allowing tunable lipophilicity and improved selectivity [29,30]. Overall, gold-based systems represent a promising direction in medicinal inorganic chemistry for developing more effective and less toxic anticancer agents (Figure 4).

Gold(I) phosphine complexes show potent cytotoxicity against colon, lung, and ovarian cancer cells, with IC₅₀ values that equal or exceed those of cisplatin [32]. Moreover, four newly synthesized mononuclear gold(I) complexes demonstrate strong activity against HeLa, PC-3, A549, and HT-1080 cell lines, with one complex reaching IC₅₀ values as low as 0.08 μM [33]. Their anticancer action involves inhibiting TrxR and disrupting ATP production, leading to cell death [31] (see Figure 5).

The anticancer potential of gold compounds was first demonstrated by Mirabelli et al. with the gold(I) complex auranofin [34]. Subsequent developments, including doxorubicin-loaded PEG-coated gold nanoparticles, showed targeted anticancer activity in vitro and in vivo [35]. Despite challenges such as toxicity, poor solubility, and drug resistance, ongoing research focuses on improving their pharmacological properties. Gold(I) phosphane and azolate phosphane complexes have emerged as particularly promising due to their strong cytotoxicity against chemoresistant tumors. Their enhanced lipophilicity promotes cellular uptake, while mechanisms involving mitochondrial dysfunction and oxidative stress allow them to overcome cisplatin resistance [36]. These properties highlight their potential as selective anticancer agents for refractory cancers. Carbene-derived gold(I) complexes, including Au(I) complex with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-thiolate, have shown strong antiproliferative effects both in vitro and in vivo. One of these new complexes shows a notably decreasing Ki67 expression, indicating substantial anticancer activity [37].

Table 1. Comparative in vitro anticancer activity of representative Au(I) and Au(III) complexes.

Compound Class	Coordination Geometry	Cancer Cell Lines	Median IC50 (µM)	In Vivo Evaluation	Key Mechanism	Reference
Linear Au(I)–phosphine	Linear P–Au–Cl	ovarian (A2780, A2780cis), colon (HCT116), lung (A549), normal human lung fibroblasts (MRC-5) cell lines	0.22–0.29 in A2780; 8–58 in A2780cis; 0.15–0.3 in HCT116; 19–31 in A549; inactive against normal cells (IC50 > 100 μM)	Not reported	Not reported	Conceição et al. [32]
Linear Au(I)–phosphine	Mononuclear and dinuclear Au(I), P-Au-C C-Au_P	cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080)	0.08–3.5	[AuL{κC-2-C6H4P(S)Ph2}] L = PTA exhibited notable antiangiogenic characteristics in an in vivo model using transgenic zebrafish Tg(fli1a:EGFP).	TrxR → ROS → apoptosis	Reddy et al. [33]
Carbene-derived gold(I) complexes	Linear C-Au-S	prostate cancer cell line (PC3)	1.2–7.4	Demonstrated significant anti-tumor effect towards prostate cancer cell line PC3.	Inhibited tumor pro-gression in mice bearing PC3 xenografts.	Walther et al. [37]
N-heterocyclic carbene (NHC) ligands	Linear C-Au-C; C-Au-Cl; Square-planar with C, I, Cl and C, I donor atoms	HCT116-p53wt, HCT116-p53wt/, OxR, 10HCT116-p53ko, HCT116-p53ko/, OxR, A2780, A2780cis, MCF-7, A375, N87	0.9–6.2	Both compounds exhibited potent antiproliferative effects against multiple cancer cell lines, including A2780, A2780cis, HCT116-p53wt, and MCF-7.	Following labeling with radioactive iodine and administration to rats, the second complex rapidly distributed to major organs within 1–5 min.	Guarra et al. 2020 [38]
gold(I) phosphine complex	bis-chelated tetrahedral [Au(d2pype)2]Cl	RPMI8226, U266 and JJN3 myeloma cells	0.25–2.6	Strongly blocked TrxR activity in myeloma cells, whether sensitive or resistant to bortezomib, which slowed their growth.	Reduced the growth of RPMI8226 myeloma tumors in NOD/SCID mice.	Sze et al. 2020 [39]
Au(III) with bulky substituents	Square-planar	Breast (MCF-7), liver (HepG2), cervical (HeLa), lung (A549) and one normal cell line (NHDF- normal human dermal fibroblasts	20.6 ± 0.98 μg/mL, MCF-7; 22.68 ± 1.13 μg/mL, HepG2; 32.00 ± 1.60 μg/mL, HeLa; 33.19 ± 1.66 μg/mL, A549	The Au(III) compound attacked cancer cells but did not harm normal cells	In vivo studies in tumor-bearing mice demonstrated the anticancer potential of the Au(III) derivative.	Sankarganesh et al. 2019 [40]
dinuclear gold(I)–gold(III) complexes	Square-planar with chelate for Au(III) (C,P,X) and linear for Au(I) (P,X)	Prostate (DU145), HeLa, Bone, (HT1080—fibrosarcoma), Hek-293T (normal, human embryonic kidney cells)	0.78–11.8 in DU145; 0.011–1.32 in HeLa; 0.062–0.46 in HT1080; 2.56–13.9 in Hek-293T	Exhibited cytotoxicity and suppressed the proliferation of multiple cancer cell lines, including HeLa and DU145.	Reduced the growth of HeLa tumors in Balb/c nude mice.	Mirzadeh et al. 2021 [41]
Au(III) with bulky substituents	Square-planar with chelate	H460, MDA-MB-231, MDA-MB-468 and BT-33	1.3–2.95	Showed toxic activity against four aggressive cancer cell types, including H460, MDA-MB-231, MDA-MB-468 and BT-33 glioblastoma at micromolar levels.	At 10 mg/kg, tumor growth in 4T1-inoculated Balb/c mice was slightly lower than in untreated mice.	Arojojoye et al. 2022 [42]

shows comparative in vitro anticancer effects of some Au(I) and Au(III) complexes and Figure 6 depicts representative Au(I) and Au(III) complexes.

Gold(III)–N-heterocyclic carbene complexes created through radioactive ¹²⁴I₂ labeling, have been used for in vivo imaging and show low-micromolar IC₅₀ values, highlighting the importance of Au(III) reduction to Au(I) for therapeutic success [38]. Structural changes in phosphine ligands significantly affect biological activity. Both auranofin and new gold complexes have effectively slowed the progression of multiple myeloma and induced apoptosis [39]. The square-planar Au complex with N-methyl-4-(trifluoromethyl)pyridine-2-amine and 4-(4-vinylphenyl)morpholine ligands displays high selectivity for cancer cells, with much lower toxicity to normal cells and IC₅₀ values between 20 and 34 μg/mL, indicating improved tumor targeting compared with cisplatin [40]. Schiff base ligands, known for their chelating ability and pharmacological effects, are widely used in Au(III) chemistry. Several Schiff base-derived Au(III) complexes have shown cytotoxicity against liver cancer models, binding through azomethine nitrogen and phenolic oxygen in square-planar structures.

Mirzadeh and colleagues developed mixed-valent Au(I)–Au(III) dinuclear complexes that specifically inhibit thioredoxin reductase and are physiologically stable [41]. Notably, mixed-valent Au(I)–Au(III) dinuclear complexes showed increased hydrophilicity, while chiral Au(III) complexes like Au(III) with bulky substituents, such as 1,2-bis[(2R,5R)-2,5-dialkylphospholano]benzene and phenylpiridine exhibited strong cytotoxic effects (IC₅₀ = 1.3–2.95 μM), prompted ROS production, mitochondrial damage, and apoptosis in aggressive cancer cell lines, and slightly slowed tumor growth in vivo, emphasizing their potential for therapy [42].

Au(III) complexes, as illustrated in

Table 2. Au-based drugs with high redox potential.

Gold Complex	Key Findings	Mechanism	References
Auranofin	ROS generation, selective redox disruption, apoptosis	TrxR inhibition	[43,44]
Au(I)-thiolates	ROS-induced mitochondrial damage, apoptosis	ROS generation, mitochondrial damage	[45,46]
Au(I)-NHC complexes	ROS generation, selective cytotoxicity, apoptosis	Redox cycling, DNA intercalation	[47]
Au(III)-pyridine	DNA intercalation, ROS-induced apoptosis	DNA interaction, oxidative stress	[48,49]
Au(III)-dithiocarbamates	ROS-induced DNA damage, apoptosis	Metal ion exchange, ROS generation	[50,51,52]
Au(III)-phosphine	Mitochondrial dysfunction, DNA binding, apoptosis	ROS generation, DNA binding	[53]

, exhibit enhanced redox properties attributable to their higher oxidation state. This characteristic enables them to interact with biomolecules such as DNA, proteins, and enzymes involved in the generation of reactive oxygen species (ROS). The Scheme 1 presented the possible mechanism of action in tumor cells.

Recent research highlights the anticancer properties of various gold-based complexes. Kumar et al. showed that Au(I) complexes with thiolate, dithiocarbamate, and Schiff base ligands exhibit strong cytotoxicity across different cancer cell lines [54]. Checconi et al. discovered new Au(I) complexes demonstrating both anticancer and antiviral activities [55]. Marinova et al. prepared Cu(II), Pd(II), and Au(III) complexes with 2-thiouracil and related derivatives, and evaluated their biological effects [56,57,58,59]. Reviews by Komeda et al., Todorov et al. and Marinova et al. focused on platinum drugs, like cisplatin, and other metal complexes—including gold, ruthenium, lanthanum, and gallium—discussing their mechanisms and therapeutic potential [60,61,62]. Wang et al. identified a pure Au(I) phosphine complex with strong cytotoxic effects on prostate cancer cells, exceeding the efficacy of cisplatin and auranofin [63].

2.1.2. Platinum-Based Anti-Cancer Compounds

Platinum-based chemotherapeutics remain central in medicinal inorganic chemistry with ongoing efforts to improve their efficacy, selectivity, and reduce toxicity. New mononuclear Pt(II) complexes with varied ligands have been developed to enhance anticancer activity across tumor models. Cis-DDP represents a key milestone in oncology first synthesized in 1844 but discovered to have biological activity in 1965 by Rosenberg who observed inhibition of bacterial cell division. This led to clinical trials in 1971 and FDA approval in 1978 establishing platinum drugs as a foundation of modern cancer therapy and influencing subsequent metal-based drug design [64,65,66,67,68].

Platinum(II)-Based Anti-Cancer Drugs

Recent studies have described a range of mononuclear Pt(II) complexes exhibiting potent anticancer activity.

Table 3. Comparative in vitro anticancer activity of representative Pt(II) complexes.

Compound Class	Coordination Geometry	Cancer Cell Lines	Median IC50 (µM)	In Vivo Evaluation	Key Mechanism	Reference
Pt(II) with bulky substituents	Square-planar with bis-chelate	SKBR3 breast cancer cells	15–39	Exhibited stronger cytotoxicity against SKBR3 cells than oxaliplatin and carboplatin.	Showed anticancer activity in a 4T1 allotransplanted breast tumor model in Balb/c mice, significantly reducing tumor volume.	Bazsefidpar et al. 2023 [69]
Pt(II) with bulky substituents	Square-planar with bis-chelate	HCT116, 4T1 and CT26.	4T1 35.6 ± 0.2 in HCT116 (IC50 25.3 ± 0.1), and CT26 (IC50 45.2 ± 0.4),	Exhibited significant cytotoxic effect against multiple cancer cell lines, including HCT116, 4T1 and CT26.	Pt(II) complex showed significant anticancer activity in an orthotopic 4T1 mouse tumor model without histopathological toxicity in the heart, lung, liver, or kidney.	Stojanović et al. 2022 [70]
cryptolepine derivatives	Square-planar with bis-chelate	T-24 cells and normal HL-7702 cells	1.3 ± 0.1 and 0.2 ± 0.2	Induced programmed cell death in T-24 cells more efficiently than cisplatin.	Administration of the Pt(II) complex (2.0 mg/kg every 2 days) reduced T-24 xenograft growth in mice.	Qin et al. 2021 [71]
α- and β-naphthyl groups	Square-planar with bis-chelate	breast cancer (MDA-MB-231 and MCF-7), lung (A549), prostate (PC3), pancreas (BXPC-3), and normal peripheral blood mononuclear (PBMC) cells	14.4 ± 1.1; 8.0 ± 1.1 (MDA-MB-231); 20.5 ± 1.1; 16.2 ± 1.2 (MCF-7); 35.3 ± 1; 18 ± 1.1 (A549); 23 ± 1.1; 14.4 ± 1.2 (PC-3); 16.3 ± 1.1; 13.7 ± 1.1 (BXPC-3); 22.0 ± 1.0; 42.0 ± 1.0 (PBMC)	Pt-13 induced cytotoxicity in multiple tumor cell lines, including A549, PC3, MDA-MB-231, MCF-7, BXPC-3, and PBMC.	Strongly suppressed MDA-MB-231 tumor xenograft growth in BALB/c nude mice.	Maciel et al. 2022 [72]
Quinoline–platinum complexes	Square-planar with bis-chelate	human osteosarcoma MG-63 cells	4–39	Quinoline–platinum complexes induced cytotoxicity in cisplatin-resistant human osteosarcoma MG-63 cells.	Inhibited growth of human osteosarcoma xenografts in mice.	Ruiz et al. 2019 [73]
Quinoline–platinum complexes	Square-planar	HeLa, A549, T24, and NCI-H460 cells	3.6 ± 0.63	Induced cytotoxicity in HeLa, A549, T24, and NCI-H460 cells more efficiently than cisplatin.	In female Balb/c nude mice, tumor xenograft growth was inhibited with efficacy comparable to cisplatin.	Mo et al. 2021 [74]

shows a comparative in vitro anticancer activity of representative Pt(II) complexes and Figure 7 depicts the structure of some of Pt(II) complexes.

Bazsefidpar et al. synthesized Pt(II) complexes with 1,3-dimethyl pentyl glycine ligand showing notable cytotoxicity (IC₅₀ = 15 μM) against SKBR3 breast cancer cells and significant anti-tumor activity in 4T1 allograft mice [69]. Stojanović et al. created Pt(II) complexes, using a 2,2-dimethylmalonic acid ligand, which displayed selective cytotoxicity and tumor suppression in vivo [70]. Qin et al. introduced new Pt(II) compounds, cryptolepine-based complexes that exhibit superior cytotoxicity (IC₅₀ = 0.2 μM), induce apoptosis through mitochondrial pathways, and more effectively reduce T-24 xenograft tumor growth than cisplatin [71]. Maciel et al. developed aPt(II) complex with a naphthyl-substituted ligand, which is highly selective for MDA-MB-231 cells, thereby reducing tumor growth in xenografts by 65.4% [72]. Ruiz et al. showed that a Pt(II) complex with hydroxyquinolate ligand impaired osteosarcoma cell viability and hindered tumor growth without causing renal or hepatic toxicity [73]. Mo et al. synthesized Pt(II) complexes with 8-hydroxyquinoline–tropolone [74]. This novel complexes demonstrated strong cytotoxicity (IC₅₀ = 3.6 μM), ROS production, cell cycle arrest, and effective tumor suppression in vivo, comparable to cisplatin [74]. Overall, these studies highlight the structural diversity and therapeutic potential of Pt(II) complexes as targeted anticancer agents.

Marinova et al. obtained Pt(II) complexes with (9′-fluorene)-spiro-5-hydantoin and (9′-fluorene)-spiro-5-(2-thiohydantoin) and examined cytotoxic activity of all compounds on the human retinoblastoma cell line WERI-Rb-1 [75]. We found that prolonged incubation periods dramatically influenced cell viability. The two Pt(II) complexes showed significant effects on cancer cell growth compared to their ligands [75]. Recently, Ahmedova et al. synthesis the new Pt(II) complexes of two 5-spiro-2,4-dihiohydantoins [76]. The antitumor activity of all compounds was tested against BV-173 (chronic myeloid leukemia-derived), HL-60, and K-562 tumor cell lines. The complexes showed modest to moderate anticancer activity as compared to cisplatin and the chronic myeloid leukemia-derived BV-173 proved to be the most responsive tumor model [76]. The in vitro data on the cytotoxicity of both spirodithiohydantoins and their complexes showed that the Pt(II) complex with (9′-fluorene)-spiro-5-hydantoin exhibits higher cytotoxicity to chronic myeloid leukemia derived BV-173 than the cisplatin. These data suggest that the class of spriodithiohydantoins hold promise as suitable ligands for the design of metal-based drugs, likewise the well-studied anticancer activity of numerous complexes of spirohydantoins [76].

Recent studies demonstrate the potential of Pt(II) complexes as anticancer agents. Dinuclear Pt(II) complexes showed strong DNA binding, overcame cisplatin resistance, and inhibited metastasis [77]. Pt(II)-ferrocene complexes selectively targeted tumor cells and suppressed xenograft growth more effectively than oxaliplatin [78]. Bis(N-heterocyclic carbene) Pt(II) complexes reduced tumor growth by 70% in vivo and overcame cisplatin resistance [79]. Naphthalenebenzimidazole-based Pt(II) complexes also exhibited greater cytotoxicity than cisplatin in selected cancer cell lines [80]. Together, these studies highlight the importance of ligand design in improving the selectivity and efficacy of platinum-based therapies.

Recent studies have focused on developing new Pt complexes that target the oxidative vulnerabilities of cancer cells (see

Table 4. Pt-based anticancer medication currently for therapy.

Platinum Complex	Redox Mechanism	Primary Target	References
Cisplatin	ROS generation, DNA damage	DNA (guanine residues)	[85,86,87,88]
Oxaliplatin	Oxidative stress, apoptosis	DNA, ROS pathways	[89,90,91,92,93]
Pt(IV) prodrugs	Redox-sensitive reduction, ROS activation	Tumor-specific reduction	[94,95]

). For instance, Pt(IV) prodrugs are reduced within cells to their active Pt(II) form, enabling precise generation of reactive oxygen species (ROS) in the hypoxic tumor microenvironment [81,82,83,84].

Recent progress in platinum-based complexes indicates that thoughtful ligand design can significantly enhance their anticancer effects, specificity, and safety compared to traditional cisplatin. While many derivatives show promising results both in laboratory and living systems, challenges remain in improving pharmacokinetics, overcoming resistance, and minimizing off-target toxicity. Future efforts should focus on detailed structure–activity relationship studies, targeted delivery strategies, and comprehensive mechanistic insights to advance these new Pt(II) complexes toward clinical application.

Platinum(IV)-Based Anti-Cancer Drugs

Pt(IV) complexes are promising anticancer agents due to their greater stability and reduced off-target toxicity compared with Pt(II) drugs. A benzoato Pt(IV) prodrug reduced tumor mass by 72.5% in a Lewis Lung Carcinoma model, although neurotoxicity was observed [96]. A Pt(IV) derivative containing a TDO inhibitor showed high potency against HepG2 cells and reduced xenograft tumor growth by 70.5% through ROS generation, apoptosis, and immune activation [97]. Mono-naproxen Pt(IV) derivatives overcame drug resistance and exhibited strong cytotoxicity with low in vivo toxicity [98]. Likewise, Pt(IV)–naproxen complexes demonstrated potent anticancer and anti-inflammatory activity, significantly suppressing tumor growth without notable toxicity [99,100]. These studies highlight Pt(IV) prodrugs as selective and effective anticancer agents with additional immunomodulatory benefits.

Cisplatin-based Pt(IV) complexes with medium-chain fatty acids as axial ligands—such as octanoate (OA) and the branched isomer valproate (VPA)—show significant antiproliferative effects in cell studies [101,102]. Novohradsky and team described a compound, [Pt(IV)diOA], with two axial OA ligands that displayed potent cytotoxicity across various tumor cell lines [103].

Table 5. Comparative in vitro anticancer activity of representative Pt(IV) complexes.

Compound Class	Coordination Geometry	Cancer Cell Lines	Median IC50 (µM)	In Vitro and In Vivo Evaluation	Key Mechanism	Reference
Benzoato Pt(IV) prodrug	octahedral	Lewis lung carcinoma (LLC)	0.11 ± 0.08	An in vivo neurotoxicity test could better ascertain the potential of compound 1 as an antitumor drug suitable for oral administration	In a murine LLC model, administration of the complex (5 mg/kg) reduced tumor mass by 72.5%.	Barbanente et al. 2022 [96]
Pt(IV) with bulky substituents	octahedral	HEPG2 cells	0.30 ± 0.025	Caused cell death in HEPG2 cells.	In mice, HepG2 tumor xenograft growth was inhibited, with activation of T cells enhancing antitumor immunity.	Hua et al. 2019 [97]
naproxen platinum(IV) complex	octahedral	A549, A549R, SKOV-3, and CT-26	2.2–66 in A549; 4.8–89.7 in A549R; 8.5–73.6 in SKOV-3; 0.2–76.8 in CT-26	Reduced growth of cancer cells such as A549, A549R, SKOV-3, and CT-26.	In BALB/c mice, CT26 tumor growth was inhibited to a level comparable with oxaliplatin and cisplatin.	Chen et al. 2020 [98]
Pt(IV) with bulky substituents	octahedral	MCF-7, MDA-MB-435, MDA-MB-231	0.17–7.0 in MCF-7; 0.16–30 in MDA-MB-231; 0.34–8.24 in MDA-MB-231	In human cancer cell lines (MCF-7, MDA-MB-435, MDA-MB-231), proliferation was inhibited and cytotoxicity induced, while MCF-7 cell migration was delayed in a wound healing assay.	In female Balb/C mice, MDA-MB-231 tumor growth was inhibited.	Jin et al. 2020 [100]

consists of comparative in vitro anticancer activity of some Pt(IV) complexes and Figure 8 depicts the structures of some investigated Pt(IV) complexes. Scheme 2 also depicts the possible mechanism of action of platinum complexes.

Marinova et al. obtained new metal complexes of (9′-fluorene)spiro-5-hydantoin and (9′-fluorene)-spiro-5-(2-thiohydantoin) with Pt(IV) and Ru(III) [104]. Unfortunately, the results for two organic ligands and its metal complexes showed that they do not have potential as antimicrobial agents against the tested Gram-positive, Gram-negative bacteria and the yeasts.

2.1.3. Ruthenium-Based Anti-Cancer Compounds

Ruthenium-based compounds have been extensively studied for their therapeutic potential due to their ability to interact with biomolecules such as DNA and proteins. Under physiological conditions, Ru(II) (d⁶, diamagnetic) and Ru(III) (d⁵, paramagnetic) are stable, with Ru(II) being more reactive and showing ligand exchange rates similar to Pt(II). Ru(II)-arene complexes, including those with 5,7-dihalogenated-2-methyl-8-quinolinol or aryl-bis(imino) acenaphthene ligands, have shown selective cytotoxicity against HeLa and CT26 cells, induced ROS production, inhibited cell migration, and reduced tumor growth in xenograft models [105,106]. New Ru(II) complexes with acylthiourea ligands were obtained [107]. All compounds were tested against different tumor cells such as A549 and A549cisR cancer lines, as well as HUVEC normal cells.

Table 6. Comparative in vitro anticancer activity of representative Ru(II) and Ru(III) complexes.

Compound Class	Coordination Geometry	Cancer Cell Lines	Median IC50 (µM)	In Vivo and in Vitro Evaluation	Key Mechanism	Reference
2-aminophenyl benzimidazole	octahedral	human breast cancer (MCF7), human colorectal cancer (Caco2), and normal human liver cell lines (THLE-2)	230–290 in MCF-7; 250–380 in Caco2; 1800–5500 in THLE-2	Exhibited cytotoxicity against multiple human tumor cell lines, including MCF-7 and Caco-2.	In the EAC mouse model, the treatment inhibited liver cancer cell proliferation by inducing apoptosis, increasing Bax and Caspase-3 levels, and decreasing Bcl-2 levels in the liver.	Elsayed et al. 2020 [108]
ruthenium(II) polypyridyl complexes	octahedral	B16, A549, HepG2, SGC-7901, HeLa, BEL-7402, non-cancer LO2	3.4 ± 0.1; 3.5 ± 0.1 in SGC-7901	The two complexes exhibited strong antiproliferative effect against SGC-7901cells.	In nude mice, SGC-7901 tumor xenograft growth was inhibited by 53.5% and 72.9% at doses of 1.23 and 2.46 mg/kg, respectively.	Chen et al. 2023 [109]
ruthenium(II) benzimidazole ligands	octahedral	A549, CH1/PA-1 and SW480 cancer cells	212 ± 24, 216 ± 5 in A549; 48 ± 4, 44 ± 7 in SW480; 56 ± 3, 55 ± 1 in CH1/PA-1	The two complexes showed moderate cytotoxicity in three human cancer cell lines in vitro in the range of the clinically studied ruthenium complex KP1019.	fac-[RuII(CO)3Cl2(N3-DMBI)] showed anticancer activity in vivo by significantly decreasing the tumor growth of a murine CT-26 colon cancer model.	Tamasi et al. 2017 [105]
Ru(II)-arene fragments to dipyridophenazine ligands	octahedral	MDAMB- 231 and HCT116 cell lines.	2.0 ± 0.6, 2.9 ± 0.8 in MDAMB- 231; 2.1 ± 0.2, 1.9 ± 0.4 in HCT116 cell lines	Displayed significant cytotoxic activity in the low micromolar range (IC50 ≈ 2–3) in MDAMB-231 and HCT116 cell lines.	TrxR → ROS → apoptosis	Nikolić et al. 2023 [110,111]
Ru(II)-compounds with aryl-bis(imino) acenaphthene chelating ligands	tetrahedral	A549, HepG2, HeLa HT29, HCT-116, SMMC-7721, and CT26.	2.3 ± 0.3, 25.6 ± 3.4 in CT26 cells;	Reduced the growth of CT26 xenografted tumor in BALB/c mice.	Accumulation of Ru(II) complex within the lysosome inducing lysosomal dysfunction in CT26 cells.	Xu et al. 2020 [106]
acylthiourea ligands	pseudo-octahedral piano-stool geometry	A549 and A549cisR cancer lines, as well as HUVEC normal cells	6.52 in A549 14.45 in cisA549R cells	Demonstrated lesser toxicity than Cis-DDP and a relatively superior survival rate of mice injected with Ru(III) compound.	Apoptosis induction and arrest the cell cycle in S-stage.	Swaminathan et al. [107]

presents a comparative in vitro anticancer activity of some Ru(II) and Ru(III) complexes. Figure 9 show the chemical structures of some Ru(II) and Ru(III) complexes.

Ruthenium complexes have demonstrated significant anticancer potential through multiple mechanisms, including DNA interaction, ROS generation, apoptosis, ferroptosis, and cell-cycle arrest. Acylthiourea-, benzimidazole-, and polypyridyl-based Ru(II) complexes exhibited enhanced cytotoxicity, particularly when delivered in liposomal formulations, while dppz-containing Ru(II)-arene complexes showed improved DNA-targeting activity and selectivity [110]. The possible mechanisms of action in tumor cells of Ru(II) and Ru(III) metal complexes are presented in Scheme 3.

Key Ru(III) compounds, including NAMI-A and KP1019/KP1339, have been extensively studied for their pharmacological properties, with KP1339 currently in clinical trials [112,113,114]. Additional Ru(II) complexes, such as hydroxyquinoline–valine and arene chlorido derivatives, displayed potent cytotoxicity (IC₅₀ = 0.3–0.71 μM), induced apoptosis and G2/M arrest, and showed selectivity toward cancer cells [115,116]. Cyclometalated and biotin-conjugated Ru(II) complexes further improved solubility, stability, organelle targeting, and phototherapeutic potential [117,118,119]. Collectively, these findings support the promise of Ru-based compounds as targeted anticancer agents, although further clinical validation is required.

Table 7. Comparison of Au, Pt, and Ru complexes as anticancer agents.

Feature	Gold Complexes	Platinum Complexes	Ruthenium Complexes
Representative compounds	Auranofin, Au(I)/Au(III) complexes.	Cisplatin, Carboplatin, Oxaliplatin.	NAMI-A, KP1019, KP1339, TLD1433.
Primary molecular target	Thioredoxin reductase (TrxR), mitochondrial proteins, cysteine- and selenocysteine-containing proteins.	Nuclear DNA (formation of DNA intra- and interstrand cross-links).	DNA, proteins, mitochondria, enzymes, and multiple signaling pathways.
Mechanism of action	Induces oxidative stress, inhibits redox homeostasis, promotes mitochondrial dysfunction and apoptosis.	DNA damage, inhibition of DNA replication and transcription, apoptosis.	Multitarget mechanism involving DNA interaction, ROS generation, enzyme inhibition, and modulation of cell signaling.
Major advantages	Effective against platinum-resistant tumors; unique non-DNA targets; strong TrxR inhibition; potential immunomodulatory effects.	Clinically validated; high efficacy against numerous solid tumors; well-established treatment protocols.	Lower systemic toxicity; selective activation in hypoxic tumors; multiple oxidation states; versatile coordination chemistry.
Major limitations	Limited clinical data; stability challenges; interactions with sulfur-containing biomolecules; relatively few approved candidates.	Nephrotoxicity, neurotoxicity, ototoxicity, myelosuppression, drug resistance, poor tumor selectivity.	Limited clinical success despite promising preclinical results; complex pharmacokinetics; no globally approved anticancer drug to date.
Drug resistance	May overcome platinum resistance through distinct molecular targets.	Frequently affected by intrinsic and acquired resistance (reduced uptake, enhanced DNA repair, drug efflux).	Generally lower cross-resistance with platinum drugs due to different mechanisms of action.
Selectivity toward cancer cells	Moderate to high, depending on ligand design and targeting strategy.	Moderate; significant toxicity toward normal rapidly dividing cells.	Generally higher owing to preferential accumulation and activation within tumor tissues.
Systemic toxicity	Generally lower than platinum complexes but dependent on ligand structure and dose.	Relatively high; dose-limiting toxicities are common.	Generally lower than platinum complexes.
Clinical development	Mostly preclinical and early clinical investigation; Auranofin is approved for rheumatoid arthritis and is being repurposed for cancer.	Multiple FDA- and EMA-approved drugs widely used in oncology.	Several candidates have entered clinical trials (e.g., NAMI-A, KP1019/KP1339, TLD1433), but no globally approved Ru-based anticancer drug.
Future prospects	Optimization of ligand stability, tumor targeting, and combination therapy.	Development of next-generation platinum drugs with reduced toxicity and resistance.	Development of multifunctional and targeted Ru complexes with improved pharmacokinetics and clinical efficacy.

presents the comparison of three discussed class complexes, as well as their mechanism of action, advantages, limitations, toxicity, clinical development and future perspectives.

Gold (Au), platinum (Pt), and ruthenium (Ru) complexes represent three important classes of metal-based anticancer agents, each possessing distinct advantages and limitations. Platinum complexes, exemplified by cisplatin and its derivatives, remain the most clinically successful metal-based chemotherapeutics due to their high efficacy against a broad range of solid tumors. However, their clinical application is limited by severe dose-dependent toxicities, acquired or intrinsic drug resistance, and lack of tumor selectivity.

Gold complexes have emerged as promising alternatives because they primarily target cellular redox systems, particularly thioredoxin reductase (TrxR), rather than DNA. This unique mechanism of action may overcome platinum resistance and can result in enhanced anticancer selectivity. Nevertheless, challenges such as limited long-term clinical validation, potential off-target interactions with sulfur-containing biomolecules, and stability issues under physiological conditions continue to restrict their clinical translation.

Ruthenium complexes offer several attractive features, including multiple accessible oxidation states, favorable ligand exchange kinetics, and the potential for selective accumulation in tumor tissues through activation in the hypoxic tumor microenvironment. Many Ru complexes also exhibit lower systemic toxicity than platinum drugs and possess multimodal mechanisms of action involving DNA, proteins, and cellular signaling pathways. Despite these advantages, no ruthenium-based anticancer drug has yet received regulatory approval, and several candidates have demonstrated limited efficacy in late-stage clinical trials.

Overall, platinum complexes remain the clinical standard due to their proven efficacy, whereas gold and ruthenium complexes offer complementary therapeutic strategies with the potential to address platinum-associated resistance and toxicity. Continued optimization of ligand design, pharmacokinetic properties, and tumor selectivity is expected to further advance the clinical development of Au- and Ru-based anticancer agents.

Although many Au-, Pt-, and Ru-based complexes exhibit potent in vitro anticancer activity, only a limited number have advanced to clinical studies. The gap between preclinical success and clinical application is primarily attributed to challenges related to pharmacokinetics, toxicity, metabolism, formulation, and drug resistance.

Many metal complexes possess unfavorable pharmacokinetic properties, including poor aqueous solubility, rapid plasma protein binding, limited tumor accumulation, and short circulation times, which reduce their therapeutic efficacy. In addition, systemic toxicity remains a major concern. While platinum drugs are associated with nephrotoxicity, neurotoxicity, and myelosuppression, newly developed Au- and Ru-based complexes generally exhibit lower toxicity but may still produce off-target effects.

Metabolic instability also limits clinical translation, as ligand exchange reactions and interactions with endogenous biomolecules, such as glutathione and serum proteins, can alter the structure and activity of metal complexes. Furthermore, formulation challenges, including poor stability and low bioavailability, often require the use of nanocarriers or targeted drug delivery systems to improve therapeutic performance.

Drug resistance represents another major obstacle. Platinum complexes commonly encounter resistance through enhanced DNA repair, reduced drug uptake, increased efflux, and intracellular detoxification. Although Au- and Ru-based complexes act through alternative molecular targets and may partially overcome platinum resistance, adaptive cellular mechanisms can still reduce their long-term efficacy.

Overall, improving pharmacokinetic properties, minimizing toxicity, enhancing metabolic stability, and developing targeted delivery strategies are essential for increasing the clinical success of metal-based anticancer agents.

2.2. Structure–Activity Relationships of Metal-Based Anticancer Complexes

The anticancer activity of metal-based complexes is governed not only by the identity of the metal center but also by the structural characteristics of the coordinated ligands. Therefore, evaluation of structure–activity relationships (SAR) provides greater insight than comparison of IC₅₀ values alone. Ligand type, coordination geometry, oxidation state, lipophilicity, and electronic and steric properties collectively determine the stability, cellular uptake, molecular targets, and overall therapeutic efficacy of metal complexes.

For gold complexes, increasing ligand stability through the incorporation of strong donor ligands, such as N-heterocyclic carbenes (NHCs) [47], generally enhances biological activity by improving resistance to ligand exchange and promoting efficient inhibition of thioredoxin reductase. The structure-activity relationships for the gold complexes are shown in Figure 10.

In platinum complexes, modifications of the carrier and leaving ligands influence DNA binding, cellular accumulation, and the ability to overcome resistance. Bulky or lipophilic ligands can improve membrane permeability and reduce susceptibility to resistance mechanisms. For ruthenium complexes, polydentate [105,106,107,108,109] and arene ligands [111] often enhance redox stability, optimize ligand exchange kinetics, and increase tumor selectivity through favorable interactions with biological targets.

Overall, highly active metal complexes typically combine appropriate kinetic stability, optimal lipophilicity, selective target recognition, and controlled ligand exchange. These observations emphasize that rational ligand design and optimization of physicochemical properties are more important determinants of therapeutic performance than low IC₅₀ values alone and should guide the development of next-generation metal-based anticancer agents.

2.3. Metal Complexes with Antimicrobial Properties

Saidin et al. reviewed a broad range of antimicrobial agents, including organic compounds (e.g., quaternary ammonium salts, guanidines, halogenated amines) and inorganic materials such as nanoparticles, highlighting their mechanisms, stability, and biomedical applications [120]. Hess similarly focused on inorganic and organometallic antibacterials, emphasizing rational design strategies based on metal reactivity and redox behavior [121]. Together, these studies illustrate the complementary roles of organic and metal-based systems in combating antimicrobial resistance.

Recent research increasingly explores organic, inorganic, and hybrid antibacterial agents. Inorganic materials such as polyoxometalates show strong activity through interactions with bacterial membranes and enzymes [122], while other metal-based drugs offer broad-spectrum effects via mechanisms distinct from conventional antibiotics [123]. Organic approaches include synthetic small molecules and modified natural polymers designed to improve stability and selectivity [124].

2.3.1. Gold(I/III)-Based Compounds with Antimicrobial Properties

Gold complexes, especially Au(I) and Au(III), have shown strong antimicrobial effects against bacteria, fungi, and multidrug-resistant strains. The FDA-approved antiarthritic medication auranofin has exhibited significant antibacterial activity, especially against Gram-positive bacteria [125,126]. Table S1 in Supplementary Materials presents the minimum inhibitory concentrations for various Au(I) and Au(III) organometallic compounds.

Auranofin exhibited a minimum inhibitory concentration (MIC) of 215–25 µg/mL against Staphylococcus aureus; however, it demonstrated substantially higher MIC values against Escherichia coli (25 µg/mL) and Pseudomonas aeruginosa (>250 µg/mL) [127]. Wiederhold et al. (2017) identified antifungal activity of auranofin against various Candida species, with MICs ranging from 25 to 16 µg/mL [126]. Torres et al. (2016) demonstrated that auranofin could effectively disrupt biofilms of S. aureus and P. aeruginosa, with minimum biofilm eradication concentrations of 99 and 24 µg/mL, respectively [125]. Numerous researchers have endeavored to synthesize auranofin analogues to broaden and enhance its antimicrobial efficacy [127,128,129,130]. Additionally, different Au(I) complexes exhibit antimicrobial properties. Frik et al. (2012) developed phosphine gold(I) complexes that demonstrated activity against E. coli, Bacillus cereus, S. aureus, and Saccharomyces cerevisiae [131]. Chen et al. (2023) reported that a series of Au(I) selenium NHC complexes effectively inhibit multidrug-resistant bacteria, occasionally surpassing auranofin in both in vitro and in vivo assessments [132].

Ndugire et al. (2022) synthesized phosphine-capped gold nanoclusters, glycosylated to produce auranofin analogues with mixed TPPMS/Ac₄ GlcSH ligand shells, thereby enhancing activity against Gram-negative bacteria and decreasing toxicity toward human A549 cells [133]. The proposed antibacterial mechanism involves DNA degradation and irreversible inhibition of cellular thioredoxin reductase, resulting in metabolic dysfunction via oxidative stress [134,135].

Organometallic complexes containing Au(III) have also been investigated for antimicrobial applications; however, their exploration has been comparatively less comprehensive than that of Au(I) complexes. Cyclometalated complexes are particularly noteworthy owing to their stability and chemical versatility [136]. One such compound, a gold(III) 1,2-thiolene cyclometalated complex, demonstrated activity against S. aureus and S. haemolyticus, and inhibited biofilm formation by these strains [137]. Chakraborty et al. (2021) documented that gold(III) complexes inhibit S. aureus, B. subtilis, and, to a lesser extent, Enterococcus faecium and E. coli [136]. Furthermore, Büssing et al. (2021) exhibited the activity of Au(III) N-heterocyclic carbene complexes against S. aureus, Klebsiella pneumoniae, E. faecium, E. coli, P. aeruginosa, and Acinetobacter baumannii [137]. Although their precise mechanism remains to be elucidated, it is probable that it involves disruption of cellular membranes [137].

Overall, gold (I) and gold (III) complexes demonstrate promising efficacy against a range of Gram-positive and Gram-negative bacteria, as well as yeasts of clinical relevance (refer to Table S2 in Supplementary Materials). Further investigations into their safety profiles and pharmacological properties may facilitate the development of novel antimicrobial agents, particularly for infections involving multidrug-resistant strains.

2.3.2. Platinum (II/IV)-Based Compounds with Antimicrobial Activities

Platinum is also present in metal complexes with various ligands. These synthesized compounds are tested for antimicrobial activity against different microorganisms (see Table S3 in Supplementary Materials). Pereira et al. (2020) studied Pt(II) complexes containing adamantane derivatives and found a notable increase in their ability to inhibit Gram-positive bacteria such as S. aureus and Bacillus cereus across all three complexes [138]. The Pt-memantine complex also showed effectiveness against E. coli, with an MIC of ≤0.14 mmol/L. In another study, three cyclometalated Pt(II) complexes were evaluated for antibacterial activity against S. aureus and MRSA (Methicillin-resistant Staphylococcus aureus) [139], all showing results that were better or comparable to the ligand. Lunagariya et al. observed enhanced antimicrobial activity in their 5-quinoline 1,3,5-trisubstituted pyrazole platinum(II) complexes compared to the ligand, indicated by lower MICs [140]. The antimicrobial efficacy of ciprofloxacin against Campylobacter jejuni was significantly improved—by an average 34.8-fold reduction in MIC—when combined with a Pt(II) complex containing 5-amino-1,3,4-thiadiazole-2(3H)-thione, and this complex alone demonstrated a stronger effect than ciprofloxacin [141]. The proposed mechanism for the antimicrobial activity of Pt(II) complexes is based on Tweedy’s chelate theory, which suggests chelation enhances the complex’s ability to penetrate the cell membrane [142].

Radić et al. studied a Pt(IV) complex with a meso-1,2-diphenyl-ethylenediamin-N,N′-di-3-propanoate ligand against various microorganisms [143]. They found it exhibited low to moderate antimicrobial activity, with MIC values from 125 μg/mL to over 1000 μg/mL and MMC values from 500 μg/mL to over 1000 μg/mL. At these concentrations, the growth of clinical isolates of S. aureus, E. coli, E. faecalis, Proteus mirabilis, Salmonella enterica, Aspergillus flavus, and Candida albicans was not inhibited [144]. A heteroscorpionate-derived Pt(IV) complex showed promise as a therapeutic agent against methicillin-resistant Staphylococcus aureus (MRSA) [145], effectively inhibiting MRSA planktonic growth—with an MIC eight times lower than that of the free ligand—and reducing biofilm formation in both standard biofilm media and wound-like conditions. Pt(IV) complexes with N-alkylphenothiazines also demonstrated activity against bacilli, MRSA, and E. coli [146]. Moreover, Frei et al. (2021) examined 14 platinum(IV) cyclooctadiene complexes, mainly showing activity against Gram-positive bacteria [146]. Ten of these compounds exhibited some activity against the bacteria in the panel and/or C. albicans and Candida neoformans, with two showing excellent effects against S. aureus, S. epidermidis, B. subtilis, and MRSA.

2.3.3. Ruthenium(II/III)-Based Compounds with Antimicrobial Activities

Ruthenium is the most prevalent element in organometallic complexes [147]. Numerous studies have explored Ru(II) complexes with various structures, including mononuclear [147,148,149], polynuclear [150,151], hetero-metallic complexes, and Ru-based carbon monoxide-releasing molecules [152,153] (see Table S3 in Supplementary Materials).

Wang et al. examined the in vitro antibacterial effects of four mononuclear Ru(II) complexes against S. aureus, reporting MICs ranging from 0.0156 to 0.2500 mg/mL [154]. The most effective complex was further studied, revealing its ability to inhibit biofilm formation and S. aureus toxin secretion, as well as to enhance the efficacy of nine commonly used antibiotics. Ointments containing this complex were also highly active in treating mouse skin infections [154]. A Ru(II) complex with 3,3′-dicarboxy-2,2′-bipyridine showed MICs of 35 µg/mL against both S. aureus and E. coli [155]. Huang et al. reported that ruthenium complexes containing phenylselenyl exhibited excellent antimicrobial activity against S. aureus (MIC 1.56–6.25 μg/mL), inhibited biofilm formation, and could clear infections in vivo in mouse and larva models [156]. The arene-Ru(II) complex synthesized by Namiecińska et al. (2020) inhibited the growth of Gram-positive bacteria, including S. aureus, S. epidermidis, and E. faecalis, but was ineffective against Gram-negative bacteria and yeasts [157]. Zhou et al. (2025) found that an aromatic ruthenium(II) complex showed significant in vitro activity against S. aureus and effectively inhibited infection in vivo in wound and sepsis models [158]. At the molecular level, it disrupted biofilm formation and reduced toxin secretion by S. aureus [158]. Gorle et al. (2014) explored the antimicrobial activity of tri- and tetra-nuclear polypyridyl ruthenium(II) complexes against four bacterial strains, including Gram-negative E. coli and P. aeruginosa, as well as methicillin-resistant S. aureus (MRSA) and Gram-positive S. aureus [159]. These complexes demonstrated excellent antimicrobial properties, with rapid uptake and high accumulation in bacterial cells, especially the tetranuclear complexes. Recent studies also show that CORMs exhibit bactericidal activity against antibiotic-resistant P. aeruginosa [160], H. pylori [161], and E. coli [162].

Stringer et al. (2017) developed a heterobimetallic complex from a Schiff base-derived isonicotinyl ferrocene using ruthenium dimers, which showed activity against Mycobacterium tuberculosis [163]. The antimicrobial properties of ruthenium (III) complexes are underexplored. Tao et al. studied ruthenium coordination polymer composites with chitosan quaternary ammonium polymers and shikimic acid, demonstrating enhanced antimicrobial effects against S. aureus compared to the free ligand and maintaining efficacy in time-kill tests [164]. These composites also inhibited S. aureus biofilm formation in a dose-dependent manner, likely by disrupting cell membrane integrity, inhibiting Ca²⁺-Mg²⁺-ATPase activity, and modulating intracellular Ca²⁺ levels. Similarly, ruthenium(III) complexes with Schiff base ligands showed higher antibacterial activity than their free ligands under similar conditions [165]. Recent reviews highlight the significance of combining organic and inorganic approaches for biomedical purposes.

Saidin et al. noted that hybrid organic-inorganic antibacterial systems can enhance therapeutic effectiveness by improving bioavailability, targeting, and reducing toxicity [119]. Natural and semi-synthetic compounds, such as polyphenols and essential oil derivatives, are also incorporated into nanomaterials to achieve synergistic antibacterial effects [166,167]. Recently, new antibacterial agents with novel mechanisms, such as disrupting cell wall biosynthesis or destabilizing membranes, have been reported, offering alternatives to combat multidrug-resistant strains [168,169]. Importantly, applied studies, including the use of organic acids to treat Staphylococcus aureus infections in poultry, demonstrate the practical potential of organic antibacterial strategies in clinical and agricultural contexts [170].

The combination of organic, inorganic, and hybrid antibacterial agents offers an exciting new direction in drug development, with the goal of creating safe, effective, and resistance-breaking treatments. Future studies should explore structure-activity relationships, develop targeted delivery methods, and conduct thorough pharmacological assessments to speed up clinical application.

3. Conclusions

This review highlights that gold, platinum, and ruthenium complexes represent complementary rather than interchangeable strategies in the development of new therapeutic agents. The evidence summarized throughout the manuscript indicates that their biological activity is strongly governed by metal identity, oxidation state, ligand architecture, redox behavior, and the nature of the biological target.

Platinum-based compounds remain the most clinically established class of metallodrugs, with Pt(II) complexes such as cisplatin, carboplatin, and oxaliplatin serving as key examples of DNA-targeting anticancer agents. However, the limitations of classical platinum chemotherapy, including resistance and systemic toxicity, have stimulated the development of Pt(IV) prodrugs and structurally modified Pt(II) complexes. Ligand modulation, axial functionalization, and redox-sensitive activation can improve tumor selectivity, enhance intracellular activation, and reduce off-target effects.

Gold-based compounds provide a distinct therapeutic paradigm. Unlike classical platinum drugs, many Au(I) and Au(III) complexes act primarily through disruption of cellular redox homeostasis, especially by inhibiting thioredoxin reductase, promoting reactive oxygen species accumulation, mitochondrial dysfunction, and apoptosis. Gold nanoparticles and gold complexes also offer opportunities for targeted delivery and theranostic applications. It should be noted that gold drugs (auranofin) have clinical precedence in non-oncological applications, while many Pt(IV) systems remain preclinical.

The ability to exploit the tumor microenvironment makes Ru(II/III) complexes attractive candidates for anticancer, antimetastatic, antimicrobial, and photodynamic applications. Ruthenium compounds may overcome some limitations of platinum drugs by targeting proteins, redox pathways, DNA, and metastatic processes. However, more consistent in vivo validation and pharmacokinetic characterization are still needed.

Overall, this review emphasizes that the future development of metal-based and hybrid therapeutic agents should move beyond simple cytotoxic screening toward a more integrated strategy that correlates chemical structure, mechanism of action, selectivity, pharmacokinetic behavior, and in vivo safety, thereby supporting the rational translation of these compounds into clinically relevant therapies.

4. Future Directions

Future research should focus on improving the selectivity, bioavailability, and safety of gold, platinum, and ruthenium complexes. A deeper understanding of their molecular mechanisms, pharmacokinetics, and interactions with biological targets will support the rational design of more effective therapeutics. In addition, advanced computational approaches, including molecular modeling are expected to accelerate the discovery of novel bioactive compounds. Finally, comprehensive preclinical and clinical studies are needed to validate the safety and therapeutic potential of these agents and facilitate their translation into clinical practice.