Synthesis, Investigation, Biological Evaluation, and Application of Coordination Compounds with Schiff Base—A Review

Abstract

Coordination compounds, characterized by the coordination of metal ions with ligands, represent a pivotal area of research in chemistry due to their diverse structures and versatile applications. This review delves into the synthesis, characterization, biological evaluation, and practical applications of these compounds. A variety of synthetic methodologies (traditional solution-based techniques) are discussed to highlight advancements in the field. Investigations into the structural, electronic, and spectral properties of coordination compounds are emphasized to provide insights into their functional attributes. The biological evaluation section focuses on their roles in antimicrobial, anticancer, and enzyme-inhibitory activities, underscoring their potential in therapeutic development. Attention is paid to nanoparticles, which are increasingly used for the treatment of oncological diseases. The metal complexes have been shown to have antibacterial, antifungal, antiviral, antioxidant, and antiproliferative properties. Additionally, the review explores their applications across domains such as catalysis, illustrating their multifaceted utility. By synthesizing recent findings and trends, this article aims to bridge the gap between fundamental chemistry and applied sciences, paving the way for innovative uses of coordination compounds in both biological and industrial contexts.

1. Introduction

Coordination compounds, formed by the interaction of metal ions with surrounding ligands, have long been a cornerstone of inorganic chemistry. Their structural diversity, arising from variations in metal centers, oxidation states, and ligand types, endows these compounds with unique physicochemical properties. These features not only provide a deeper understanding of chemical bonding and reactivity but also enable a wide range of applications spanning biological, industrial, and environmental fields. The synthesis of coordination compounds has evolved significantly, leveraging both conventional and modern techniques to optimize their yield, stability, and functionality (see Scheme 1, Scheme 2 and Scheme 3). Characterization methods, such as spectroscopic, crystallographic, and electrochemical analyses, play a critical role in unraveling their structural intricacies and guiding their application.

To date, numerous metal complexes of different organic ligands were synthesized using Scheme 1 [1,2,3,4,5,6,7,8,9,10,11,12] or Scheme 2 [13,14,15,16,17,18,19,20,21,22,23,24,25,26].

To date, numerous metal complexes of spirohydantoins [1,2,3,4,5], thiouracils [6,7,8], and other derivatives [10,11,12,27,28,29] were synthesized and their composition and structure with various metals like copper, nickel, zinc [1,2,12,30], as well as palladium, platinum, and gold was studied [6,7,8,9]. Spirohydantoins are polycyclic compounds with a single atom (usually carbon) as the only common member of two rings. Spirohydantoins are a novel class of aldose reductase inhibitors characterized by very potent in vivo activity. Several of these (phenytoin, methetoin, fosphenytoin, norantoin, mephenythoin) are well-known anticonvulsive drugs, whereas others have been suggested to have antimicrobial and antiarrhythmic effects. Thiouracil is a molecule that belongs to a family of compounds based on its structure, known for its use as an anti-thyroid agent and coronary vasodilator, but abandoned due to its high frequency of adverse reactions like agranulocytosis. What these two classes of compounds have in common is that they possess O, N, and S donor atoms in their molecules and are important biologically active substances. On the other hand, metal ions such as copper, zinc, cobalt, platinum, gold, etc., are also of great importance to the human body. It is believed that when an essential element interacts with a biological ligand, the resulting complex would hypothetically have a more pronounced biological effect than the ligand itself. Summary data on the structure of the complexes with spirohydantoins, thiouracils, and similar derivatives and the donor atoms involved in the coordination are given in

Table 1. Metal complexes of spirohydantoins, thiouracils, and similar derivatives with different metal ions.

Technique	Donor Atom	Metal	Structure	References
13C CPMAS NMR, IR and FAB-MS and theoretical DFT studies	N3^S4-bridging coordination	Cu(I) and Ni(II)	dimeric structures	[1]
13C CPMAS NMR and theoretical DFT studies	N3^S2-bridging coordination for cyclohexanespiro-5-(2,4-dithiohydantoin with Cu(I); monodentate coordination (N3- and S2-) of two non-equivalent ligand molecules for cyclooctanespiro-5-(2,4-dithiohydantoin) with Cu(I); N3^S4- bridging way for Ni(II)	Cu(I) and Ni(II)	dimeric structure for Cu(I) with cycloheptanespiro-5-(2,4-dithiohydantoin); square planar for Ni(II) with cycloheptanespiro-5-(2,4-dithiohydantoin) and cyclooctanespiro-5-(2,4-dithiohydantoin)	[2]
IR and 13C CPMAS NMR and theoretical DFT studies	N and S	Pt(II)	square planar	[3]
13C-NMR-CP-MAS, EPR, IR and quantum-chemical (DFT/B3LYP-6-31G (d,p)) methods	N for Cu(II) and N3 and S2 for Ni(II)	Cu(II) and Ni(II)	distorted tetrahedral for Cu(II) and square planar for Ni(II)	[4]
13C CPMAS NMR and theoretical DFT studies, X-ray	O, Cl	Al(III)	six-membered chelate rings	[5]
melting point analysis, MP-AES for Cu and Pd, UV-Vis, IR, ATR, 1H NMR, 13C NMR and Raman, Solid-state NMR spectroscopy	O, S for 6-methyl-2-thiouracil and S for 6-propyl-2-thiouracil with Cu(II); N, S, O with Pd(II)	Cu(II) and Pd(II)	tetrahedral for Cu(II) with 6-methyl-2-thiouracil and octahedral for 6-propyl-2-thiouracil; chelate for Pd(II) with 6-methyl-2-thiouracil and 6-propyl-2-thiouracil	[6]
MP-AES for Cu and Au, ICP-OES for S, ATR, solution and solid-state NMR, and Raman spectroscopy	N,S for Au(III) and O,S for Cu(II)	Au(III) and Cu(II)	chelate structure	[7]
UV-Vis, IR, ATR, 1H NMR, HSQC, and Raman, solid-state NMR spectroscopy	O, S	Au(III)	tetrahedral	[8]
IR, FAB-MS, XPS, solid-state NMR spectroscopy and theoretical DFT studies	N, S	Pt(II)	dimer, chelate structure	[9]
X-ray	O, N	Ag(I)	dinuclear complex, chelate structure	[10]
X-ray, ESR, MALDI mass-spectrometry, NMR spectroscopy	P, O, P	Ru(II) and Ru(III)	chelate structure	[11]
X-ray and 1H-, 13C-NMR, IR and UV-Vis spectroscopy and elemental analysis and theoretical DFT studies	O, N	Cu(II), Fe(II) and Zn(II)	chelate structure	[12]
elemental analysis, FAAS, FT-IR, MS, TG methods and X-ray for C3 and C4	N, Cl	Zn(II)	tetrahedral geometry, dinuclear coordination compounds	[30]
Elemental analysis, NMR and ESI-MS	C, Cl	Rh(I) and Ru(II)	Tetrahedral or square planar	[31]
X-ray and 1H-, 13C-NMR, IR and UV-Vis spectroscopy and elemental analysis	C, Cl	Au(III)	square planar	[32]
NMR and mass spectroscopy, X-ray	C, Cl	Au(I) and Ag(I)	Linear	[33]

.

One of the most intriguing aspects of coordination compounds is their biological relevance. Many of these compounds exhibit promising activities, including antimicrobial, anticancer, and enzyme-inhibitory properties, positioning them as candidates for therapeutic development. Furthermore, their roles in catalysis, molecular sensing, and environmental remediation underscore their significance in addressing global challenges. This review provides a comprehensive exploration of the synthesis, investigation, biological evaluation, and applications of coordination compounds. By integrating insights from recent studies and emerging trends, it aims to illuminate the potential of these compounds to advance science and technology. The key characteristics of transition metals and their complexes are as follows. 1. Charge Variation: Transition metals can exist as positively charged species in aqueous solutions, with charges adaptable based on their coordination environment. This enables binding to negatively charged biomolecules, which is critical in therapeutic applications [34]. 2. Structural Diversity: Transition metal complexes can adopt a wide range of coordination geometries and bond configurations. This flexibility allows for unique shapes and molecular interactions, surpassing conventional carbon-based compounds [34,35,36,37]. 3. Metal–Ligand Interactions: These interactions form unique complexes with distinct thermodynamic and kinetic properties, enhancing ligand exchange reactions and biological compatibility [34]. 4. Lewis Acid Properties: The high electron affinity of transition metals facilitates the polarization and hydrolysis of coordinated groups, contributing to their catalytic activities [34,35]. 5. Partially Filled Shells: The electronic configurations of transition metals impact their magnetic and electronic properties, which are crucial for biochemical functions [35]. 6. Redox Activity: Transition metals readily undergo redox reactions, a vital feature in biochemical redox catalysis and drug design [35].

Coordination compounds, formed by the interaction of metal ions with surrounding ligands, have long been a cornerstone of inorganic chemistry. Their structural diversity and physicochemical properties not only advance our understanding of chemical bonding but also enable applications across biological, industrial, and environmental fields. Among these, Schiff base coordination compounds have garnered particular attention due to their versatile synthesis, tunable properties, and wide-ranging biological relevance. Despite the growing body of research on these compounds, several challenges remain unaddressed. These include optimizing synthetic routes for specific applications, improving the stability of complexes, and advancing their therapeutic and catalytic potential. Existing reviews in the field have primarily focused on either general coordination chemistry or isolated aspects of Schiff base ligands. However, there is a lack of an integrated perspective that encompasses their synthesis, investigation, biological evaluation, and diverse applications. This review aims to fill this gap by providing a comprehensive exploration of Schiff base coordination compounds, integrating insights from recent studies and emerging trends. By critically analyzing their structural diversity, biological activity, and practical applications, this work seeks to illuminate their potential to drive advancements in science and technology. This review aims to assist researchers primarily focused on inorganic synthesis and to highlight the untapped potential of ligand molecules such as Schiff bases. It is important to note that, while this review includes literature published over the past two decades, it is not possible to cover all available data in a single work. In selecting studies, we considered the potential for biological applications relevant to researchers in this field, as well as the properties of transition metals. The review examines complexes involving both commonly studied metals from essential elements (Cu, Zn, Co, Fe) and non-essential elements (Ru, Rh, Pd, Pt, Ni, Ag, Au, Hg, Cd). The benefit of this review is that various literary sources have been utilized to highlight the biological significance of the synthesized compounds, rather than concentrating on just one or two metal ions, as observed in other reviews.

2. Methods for Characterization of Coordination Compounds

Characterization of coordination compounds involves determining their chemical composition, structural properties, and electronic behavior to understand their reactivity, functionality, and applications. Several analytical and spectroscopic methods are employed to explore these aspects. Techniques such as X-ray crystallography [38,39,40,41,42,43,44,45,46,47,48,49] are central to determining the three-dimensional arrangement of atoms, providing precise geometrical details about the coordination sphere. UV-Vis spectroscopy [50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80] is used to study the electronic transitions within the metal–ligand complexes, offering insights into the ligand field and electronic structure. Infrared (IR) spectroscopy identifies functional groups and bond vibrations, highlighting the types of ligands present and their binding modes [81,82,83,84,85,86,87,88,89,90]. Additionally, NMR spectroscopy (solid state or in solution) [91,92,93,94,95,96,97,98,99,100,101,102,103] can probe the chemical environment of nuclei within the ligands, especially in diamagnetic complexes. Other techniques like elemental analysis, mass spectrometry, and thermogravimetric analysis (TGA) provide quantitative data on the composition, stability, and thermal properties. Cyclic voltammetry and related electrochemical methods help in understanding redox behavior, while magnetic susceptibility measurements reveal information about unpaired electrons and the magnetic properties of the metal center. These techniques together provide a comprehensive understanding of coordination compounds, supporting their design and application in areas such as catalysis, medicine, and materials science. Some spectroscopic methods for investigation of coordination compounds are given in Scheme 3. Scheme 3 includes electronic and vibrational spectroscopy, NMR in solution or in the solid state, and X-ray structural analysis.

The biochemical properties of ruthenium compounds were initially identified in the 1950s, and reports of their anticancer potential emerged during the 1960s. The first ruthenium-based drug candidate for cancer therapy to enter clinical testing was NAMI-A, which was later succeeded by KP1019 in 2003. Nickel enhances the synthesis of sulfur-containing amino acids. Nickel (in an unknown oxidation state) enters the active site of the enzyme urease, which facilitates the hydrolysis of urea. Complexes of Co and Ni with thiosemicarbazones and Schiff bases are known to exhibit weak bactericidal properties. Nickel is found in very small amounts in the blood, adrenal glands, brain, kidneys, lungs, skin, bones, and teeth. The element is concentrated in those organs and tissues in which intensive exchange processes, biosynthesis of hormones, vitamins, and other biologically active compounds take place. Copper is one of the most essential elements in microbiology. In trace amounts, copper facilitates numerous biochemical processes in living organisms. A deficiency of copper ions (Cu²⁺) leads to anemia in humans and hinders nitrogen uptake in plants. In the human body, it is primarily located in the liver and certain regions of the brain. Several of metal complexes with Pt, Ru, Rh, Cu, Ni, Co, Zn, etc., are well-known antitumor drugs, whereas others have been suggested to act as antimicrobial and anti-inflammatory properties. Zhang et al. obtained caffeine-derived rhodium(I) N-heterocyclic carbene complex [31]. Maroto-Díaz et al. synthesized and evaluated the anticancer activity of carbosilane metallodendrimers based on arene ruthenium (II) complexes [104]. El-Tabl et al. reported the synthesis, characterization, and anticancer activity of new metal complexes derived from 2-Hydroxy-3-(hydroxyimino)-4-oxopentan-2-ylidene benzohydrazide [105]. The structure of ruthenium and rhodium complexes [101,104] and Cu(II), Ni(II), Co(II), Zn(II), and Cd(II) [105] are given in Figure 1 and Figure 2 and Figure 3, respectively.

Raducka et al. described a series of metal complexes with that are beneficial for health as being zinc, and bioactive ligands, and benzimidazole derivatives [30]. By way of synthesis authors have obtained four coordination compounds named C1, C2, C3, and C4. X-ray analysis for C3 and C4 have been used to establish the structure of metal complexes with Zn(II) [30]. The molecular structures of two complexes are presented in Figure 4.

Strong stereospecific intramolecular H-bonding between an en NH proton oriented away from the arene and the C60 carbonyl of G is present in the crystal structures of Ru–arene adducts of 9-ethylguanine (9EtG) and guanosine (Figure 5; average N…O distance 2.8 A˚, N–H…O angle 163u) [106].

The molecular structures of Ru and Au complexes are presented in Figure 6 and Figure 7 and Figure 8, respectively.

3. Some Aspects of the Biological Significance of Coordination Compounds with Schiff Base

Recently, Soroceanu et al. presented biomedical application of coordination compounds with Schiff base ligands [108]. Raducka et al. provides insight into the structural and biological evaluation of zinc-based coordination compounds with benzimidazole derivatives [30]. Ndagi et al. evaluated the anticancer therapy with coordination compounds [109]. Possible biological applications of coordination compounds are given in Figure 9 and Figure 10. Figure 9 illustrates various biological and catalytic activities associated with ligands and coordination compounds containing Schiff bases. These activities include anti-inflammatory activity, catalytic and antitumor, antimicrobial, and analgesic activity. Figure 10 indicates their potential in cancer treatment, with a focus on developing compounds with anticancer properties. This visual categorization underscores the versatility of Schiff base coordination compounds, linking their structural diversity to their multifaceted roles in biological and chemical applications.

Figure 10 represents a comprehensive approach to the development, characterization, and evaluation of coordination compounds, bridging chemistry with biological and computational sciences.

Schiff base metal complexes have garnered significant attention in the fields of biological and inorganic chemistry due to their promising biological activities, particularly in the development of therapeutic agents for various bacterial infections. Schiff bases, which are derived from the condensation of primary amines with carbonyl compounds, often serve as effective ligands for transition metals. These metal complexes mimic biologically relevant species, making them valuable models for studying enzyme mechanisms and other biological processes. Many Schiff base metal complexes demonstrate antimicrobial properties, showing efficacy against a wide range of bacterial strains, including both Gram-positive and Gram-negative bacteria [30,108,110]. The ability of these complexes to interact with biological molecules, such as enzymes and DNA, enhances their therapeutic potential, particularly for the treatment of bacterial diseases. For instance, Schiff base complexes of metals like copper, iron, and zinc have been extensively studied for their antibacterial, antifungal, and anticancer activities [30,108,110]. The biological relevance of Schiff base metal complexes also extends to their use as models for metalloenzymes, which are critical in various biochemical processes. These complexes can be designed to simulate the active sites of enzymes, allowing researchers to investigate the mechanisms behind their biological activity and to develop more targeted therapeutic agents. In summary, Schiff base metal complexes represent a promising avenue for the design of new antibiotics and other therapeutic agents due to their biological activity and ability to mimic biologically significant species.

3.1. Anticancer Properties

3.1.1. Therapeutic Potential in Cancer Treatment

Transition metal-based compounds, such as platinum-based drugs (e.g., cisplatin), have demonstrated notable success in cancer therapy due to their ability to perform the following:

• − Exhibit redox activity;
• − Form complexes targeting specific biomolecules;
• − Disrupt cellular mechanisms of proliferation.

Emerging research continues to focus on synthesizing new metal-based compounds with enhanced selectivity, reduced toxicity, and improved efficacy. These include compounds that modulate cellular mechanisms via novel pathways, offering hope for more effective cancer treatments (see Figure 11, Figure 12 and Figure 13). Figure 11 underscores the role of Schiff base metal complexes in mediating biological effects via dual mechanisms (caspase and ROS activation). Their ability to induce targeted cell death highlights their potential in therapeutic development, particularly in cancer treatment.

Figure 12 appears to represent a mechanistic pathway illustrating the biological activity of a coordination compound (likely containing a metal, such as gold (Au)) leading to cell death through specific processes.

A novel series of gold(I)–N-heterocyclic carbene (NHC) complexes derived from xanthine-based ligands have been synthesized and analyzed using mass spectrometry, NMR, and X-ray crystallography [111]. These compounds were evaluated for their antiproliferative effects on human cancer cells and non-cancerous cells in vitro, as well as their toxicity on healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)₂][BF₄] (complex 4) demonstrated selectivity toward human ovarian cancer cell lines while exhibiting low toxicity in healthy tissues [111]. To obtain preliminary understanding of their potential mode of action, two biologically significant cellular targets were examined: DNA (specifically a higher-order DNA structure called G-quadruplex DNA, which has critical roles in oncogene regulation) and a key enzyme in the DNA damage response (DDR) system (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), which is heavily implicated in cancer resistance mechanisms) [111]. The authors findings suggest that the [Au(caffein-2-ylidene)₂][BF₄] complex functions as a potent and selective G-quadruplex binder, while being a moderate PARP-1 inhibitor (i.e., a weak DDR-disrupting agent), thereby shedding light on the molecular mechanism underlying its antiproliferative activity [111].

The chlorido(η²,η²-cycloocta-1,5-diene)(1,3,7,9-tetramethylxanthine-8-ylidene)rhodium(I) (complex 1) in Figure 13 inhibits TrxR, which in turn leads to an accumulation of ROS that most likely damage DNA and so initiate cell cycle arrest and apoptosis. The structure of complex 1 is given in Figure 1.

Several metal-based compounds have been synthesized, with promising anticancer properties. Some of these are already used in clinical practice for diagnosis and treatment, while others are still undergoing clinical trials. Recently, synthesized metal-based compounds are the result of targeted drug design aimed at achieving specific goals that the original compound could not. These new compounds display a different spectrum of cytotoxicity. The cytotoxic effect of the newly developed compounds, assessed as potential anticancer agents, was evaluated against adenocarcinoma (A549), neuroblastoma (SK-N-AS), glioblastoma (T98G), and lung cell cultures, along with normal human skin fibroblasts (CCD-1059Sk) [30]. The prediction results for the free ligand L3 (2-(Pyridin-3-yl)-3H-imidazo [4,5-b]pyridine) and L4 (6-Bromo-2-(pyridin-3-yl)-3H-imidazo [4,5-b]pyridine) are given in

Table 2. Cancer cell line prediction results for the ligand. Pa (probability “to be active”); Pi (probability “to be inactive”) [30].

Ligand	Pa	Pi	Cell-Line Name	Tissue	Tumor Type
* L3	0.587	0.029	Oligodendroglioma	Brain	Glioma
L3	0.538	0.010	Colon adenocarcinoma	Colon	Adenocarcinoma
L3	0.490	0.022	Non-small-cell lung carcinoma	Lung	Carcinoma
L3	0.475	0.009	Pancreatic carcinoma	Pancreas	Carcinoma
L3	0.439	0.043	Pancreatic carcinoma	Pancreas	Carcinoma
* L4	0.559	0.006	Pancreatic carcinoma	Pancreas	Carcinoma
L4	0.554	0.009	Colon adenocarcinoma	Colon	Adenocarcinoma
L4	0.415	0.038	Cervical adenocarcinoma	Cervix	Adenocarcinoma
L4	0.426	0.099	Oligodendroglioma	Brain	Glioma

* L3—2-(Pyridin-3-yl)-3H-imidazo [4,5-b]pyridine; * L4—6-Bromo-2-(pyridin-3-yl)-3H-imidazo [4,5-b]pyridine.

and the cytotoxic effects of metal complexes are presented in

Table 3. Cytotoxic effect of the metal complexes against glioblastoma (T98G), neuroblastoma (SK-N-AS), lung adenocarcinoma (A549) cell lines, and human normal fibroblasts (CCD-1059Sk) determined by MTT assay after 24 h incubation. IC50 ± SD (µg/mL) [30].

Complex	T98G	SK-N-AS	A549	CCD-1059-Sk
* L1	41.25 ± 2.30	>100	>100	>100
C1	32.22 ± 0.92	35.59 ± 1.03	33.51 ± 1.29	18.42 ± 0.37
* L2	34.98 ± 1.44	81.35 ± 3.31	43.08 ± 2.17	>100
C2	24.29 ± 0.11	33.72 ± 0.39	34.44 ± 0.75	27.27 ± 1.05
L3	>100	>100	>100	>100
C3	46.54 ± 1.86	41.60 ± 1.93	41.34 ± 2.17	30.84 ± 1.11
L4	>100	>100	>100	>100
C4	30.05 ± 1.81	36.17 ± 0.44	35.01 ± 0.86	33.62 ± 0.85
Etoposide	>100	67.83 ± 2.03	>100	>100

* L1—2-(Pyridin-4-yl)-3H-imidazo [4,5-c]pyridine; * L2—2-(Pyridin-4-yl)-3H-imidazo [4,5-b]pyridine.

.

Recently, Nandaniya et al. presented a mini review with biological application of Schiff base metal complexes [112]. The text explores both the challenges and advancements related to the safety and efficacy of metal complexes in cancer therapy and the innovative role of nanotechnology in addressing these issues. Below is a summary of the main points.

3.1.2. Safety Issues with Metal Complexes

1.

Toxicity Challenges: Despite their effectiveness, metal-based cancer drugs like cisplatin are associated with severe side effects, including nephrotoxicity, neurotoxicity, and ototoxicity [113]. These challenges have spurred the development of derivatives such as carboplatin, which, while promising, still face regulatory hurdles due to adverse effects.

2.

Examples of Failed Derivatives: Several platinum-based drugs (e.g., JM-11, ormaplatin, zeniplatin, and spiroplatin) failed to gain market approval due to severe or unpredictable toxicities [114].

3.

Gold and Copper Complexes: Gold(III) complexes, while studied for anticancer applications, can cause toxicity, particularly affecting skin and mucous membranes [115]. Elevated copper levels have been linked to cancer progression, further underscoring safety concerns [116].

4.

Strategies to Mitigate Toxicity: Structural modifications of metal complexes aim to improve their selectivity for cancer cells and reduce adverse effects on healthy tissues.

3.1.3. Nanoparticles in Cancer Therapy

1.

Advantages of Nanotechnology: Nanoparticles (NPs) offer targeted drug delivery, improving therapeutic index and reducing off-target effects [117]. They enhance bioavailability, solubility, and stability while facilitating sustained release and selective targeting of cancer cells.

2.

Metal-Based Nanoparticles: Metal-based NPs (e.g., nickel, gold, silver, iron oxide, gadolinium) provide significant advantages in drug delivery and diagnosis due to their large surface area, which can carry higher drug loads.

3.

Tumor-Specific Targeting: NPs can be functionalized with peptides, proteins, nucleic acids, or small molecules to target tumor-specific receptors or biomarkers, ensuring precise delivery [118]. This reduces toxicity in non-cancerous tissues.

4.

Imaging and Therapeutic Applications: NP-based platforms are used for advanced optical imaging and therapeutic delivery. Their multifunctional nature enables combined diagnostic and therapeutic applications, paving the way for synergistic effects when combined with multidrug regimens.

While metal complexes remain a cornerstone of cancer treatment, their clinical use is often limited by toxicity and side effects. Innovations in nanotechnology provide a promising pathway to enhance the safety, efficacy, and specificity of metal-based cancer therapies, offering a brighter future for targeted and less toxic treatments.

3.2. Antimicrobial Activity (Antibacterial and Antifungal)

In recent years, particularly from 2015 onwards, Schiff base metal complexes have garnered significant interest due to their noteworthy biological properties. Numerous studies have been published highlighting their applications in biological sciences [119,120]. Schiff bases have demonstrated potential as antibacterial agents, with their metal complexes exhibiting superior antibacterial activity compared to the free ligands themselves [121,122,123,124,125,126]. Recent literature underscores the promising antimicrobial potential of Schiff base metal complexes and highlights progress in the study of other intriguing topoisomerase inhibitors [127]. For instance, the Cu(II)–picolinic acid complex has been shown to act as a significant inhibitor in gel electrophoresis experiments [128]. Additionally, thiosemicarbazone derivatives of copper(II) have exhibited strong antibacterial activity, effectively targeting pathogens such as S. aureus, S. typhimurium, and K. pneumoniae after just six hours of incubation [129]. Literature reviews show that Schiff bases with antibacterial properties can be synthesized from coordination compounds with different ligands such as indole [130,131], pyridine [132,133,134], isatin [134,135,136], hydrazide [137,138], benzimidazole [139,140], thiazolidiones [141,142], thiazole [143], thiosemi-carbazone [144,145], lysine/curcumin [146,147], and siloxane [148]. Further examination of the literature reveals a significant rise in systemic fungal infections, which can be life-threatening [149]. Numerous studies highlight that Candida species (both albicans and non-albicans) and Aspergillus species (Asp.) are responsible for causing the most severe fungal infections [150,151,152,153,154]. Consequently, the development of new antifungal agents with reduced resistance and increased effectiveness has become a priority [155,156]. Extensive and meticulous research has been conducted, with several Schiff ligands identified as highly effective antifungal agents [157,158]. Researchers have also pointed out that specific groups, such as methoxy, halogen, and naphthyl, enhance the fungicidal activity of these ligands [159,160]. While still widespread, the recent literature strongly emphasizes the promising potential of metal complex-based antifungal drug development [161,162]. In another study, Schiff base ligands and their mononuclear chelate complexes, incorporating metals like Cr(III), Fe(III), Mn(II), Cu(II), Zn(II), Ni(II), and Cd(II), were synthesized from the 4-((1-5-acetyl-2,4-dihydroxyphenyl)ethylidene) amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one ligand, a tridentate ligand. These complexes were used for in vitro tests to assess their antimicrobial activity against both Gram-negative and Gram-positive bacteria, as well as fungal organisms. In this research, the MOE 2008 software was used for drug screening by molecular docking at protein sites of the novel coronavirus, and the study included molecular docking validation through MD simulations [163]. The antimicrobial potential of zinc complexes, their unbound ligands, and standard drugs was examined against six strains of Gram-positive bacteria, five Gram-negative bacterial strains, and three yeast strains [30]. The minimum inhibitory concentrations (MICs) of the tested derivatives were determined against a panel of reference microorganisms from the American Type Culture Collection (ATCC). The panel included Gram-negative bacteria such as Escherichia coli (ATCC 25922), Salmonella Typhimurium (ATCC 14028), Klebsiella pneumoniae (ATCC 13883), Pseudomonas aeruginosa (ATCC 9027), and Proteus mirabilis (ATCC 12453). Gram-positive bacteria tested included Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 12228), Micrococcus luteus (ATCC 10240), Enterococcus faecalis (ATCC 29212), Bacillus subtilis (ATCC 6633), and Bacillus cereus (ATCC 10876). The antifungal activity was assessed against Candida albicans (ATCC 10231), Candida parapsilosis (ATCC 22019), and Candida glabrata (ATCC 90030). The antibacterial and antifungal efficacy was quantified using the minimum inhibitory concentration (MIC), expressed in milligrams per liter. The activity of zinc complexes was compared to the antimicrobial profiles of their corresponding ligands. Vancomycin (Van), ciprofloxacin (Cip), and nystatin (Nys) were employed as reference standards. The evaluated compounds demonstrated no activity against Gram-negative bacteria and yeasts. However, against Gram-positive bacteria, moderate activity was observed, with a slight enhancement in bioactivity for the zinc complexes [30].

3.3. Antioxidant Activity

There has been considerable interest in discovering compounds with antioxidant properties (see Figure 14). While natural antioxidants are typically the most costly, researchers have turned to synthetic antioxidants as a more cost-effective and efficient alternative. As a result, various metal complexes have been studied for their ability to act as effective scavengers of reactive oxygen species (ROS), functioning as antioxidants [164].

In a study by Devi and colleagues [165], 16 novel Ni(II), Cu(II), Co(II), and Zn(II) metal complexes were synthesized starting from 4 Schiff base ligands. These ligands were created through a condensation reaction involving 4-(benzyloxy)-2-hydroxybenzaldehyde and various aminophenol derivatives. The antioxidant properties of these metal(II) complexes were evaluated in vitro, and the results revealed that the complexes exhibited notable potential (see Figure 15). Particularly, the Cu(II) complexes displayed excellent antioxidant activity, significantly decolorizing the purple DPPH solution, with an IC₅₀ value ranging from 2.98 to 3.89 µM, which was more effective compared to the free ligands.

A range of Schiff base compounds, derived from diamine, sulfanilamide, hydroxyquinoline, thiocarbohydrazide, and benzohydrazide, with substituted ketone or aldehyde groups, as well as their Co(II), Zn(II), Cu(II), Fe(II), Ni(II), Pd(II), Cd(II), and Ru(II) metal complexes, have been examined for their antioxidant potential. Compounds with methyl and nitro groups exhibited stronger antioxidant activity compared to those with 4-hydroxy groups, leading to an enhancement in antioxidant performance [166,167]. A study conducted by Inan et al. demonstrated the antioxidant activity of these complexes using the L-ascorbic acid-standard method (DPPH) [168]. The complexes showed greater activity than the ligands themselves, likely due to the coordination of the metal ion with the organic ligand [169]. Specifically, [Cu(II)-(furfural-MAP)₂Cl₂] and [Ni(II)-(furfural-MAP)₂Cl₂] showed significant antimicrobial activity, while [Zn(II)-(furfural-MAP)₂Cl₂] displayed moderate activity. The variance in antioxidant activity among the complexes was attributed to differences in their coordination sphere and redox properties [170]. Kizilkaya et al. explored the antioxidant capabilities of Schiff bases synthesized using ABTS radical scavenging and DPPH free radical scavenging methods [171]. The synthesized compounds demonstrated good antioxidant activity, suggesting their potential as synthetic antioxidant agents.

3.4. Enzyme-Inhibitory Activities

Che et al. presented the metal complexes in medicine with a focus on enzyme inhibition [171]. Metal complexes containing labile ligands have long been recognized for their ability to undergo ligand-substitution reactions with biomolecular targets (see Figure 16).

These metal ions interact with nitrogen, sulfur, or selenium atoms in histidine, cysteine, or selenocysteine residues found in proteins, often resulting in therapeutic effects. Some notable examples include auranofin, a gold(I) phosphine complex (illustrated in Figure 17) that is an established drug for managing rheumatoid arthritis. Recent findings indicate that gold from auranofin can transfer to the selenoprotein thioredoxin glutathione reductase, producing therapeutic effects against parasitic diseases. Additionally, auranofin demonstrated tumor cell growth inhibition in vitro [172]; however, its high reactivity with protein thiols limits its antitumor efficacy in vivo [173]. New research highlights a gold(I)–phosphine complex with a naphthalimide ligand as a potent thioredoxin reductase inhibitor with significant antiproliferative and anti-angiogenic activities [174]. Furthermore, studies on a gold(III)–dithiocarbamate complex (depicted in Figure 17) identified the proteasome as its main target [175], showing promise in therapeutic applications.

Platinum: Selenoenzyme thioredoxin reductase has been identified as a target effectively inhibited by (2,2′:6′,2′′-terpyridine)platinum(II) complexes (shown in Figure 17) with IC₅₀ values at the nanomolar level [176]. Recently, research by Lo et al. employed X-ray crystallography and mass spectrometry to demonstrate that aromatic thiolato platinum(II)–terpyridine complexes inhibit human thioredoxin reductase 1 by blocking its C-terminal active-site selenocysteine [177]. Furthermore, a series of platinum(II)–terpyridine complexes exhibited inhibitory activity against topoisomerase II (top2). The mechanisms of top2 inhibition are diverse, involving DNA intercalation, enzyme binding, and modification of enzyme thiol groups. As such, these platinum(II)–terpyridine complexes are thought to inhibit topoisomerase II by ligand exchange reactions with the thiol groups of enzymes [177]. Additionally, a series of platinum(II) complexes with two or three labile ligands (PtCl₂(smp), Figure 17) demonstrated inhibitory effects on matrix metalloproteinase-3 (MMP-3) [178].

Ruthenium: A novel class of glutathione transferase inhibitors (denoted as Ru–EA, shown in Figure 17) was synthesized by coupling ethacrynic acid (EA), a potent glutathione transferase inhibitor, with a ruthenium complex [179]. Analysis using mass spectrometry and X-ray crystallography revealed that the Ru–EA complex initially loses two chloride ligands, followed by cleavage to release a ruthenium-containing fragment (see Figure 18). Overall, metal complexes with labile ligands predominantly target proteins featuring selenocysteine or cysteine in their active sites, such as thioredoxin glutathione reductase, thioredoxin reductase, and glutathione transferase. The ruthenium complex as glutathione transferase inhibitor is given in Figure 19.

A notable limitation of the metal complexes mentioned earlier is their lack of selectivity. These complexes often interact with human serum albumin or other proteins that have potential metal-binding sites, such as histidine, cysteine, or selenocysteine. Such interactions make it challenging to deliver metal complexes to specific biomolecular targets. For instance, while auranofin is known to inhibit thioredoxin glutathione reductase and suppress tumor cell growth in vitro [172], its strong reactivity with protein thiols significantly reduces its antitumor efficacy in vivo [173]. To address this, Berners-Price and Filipovska developed a series of gold(I) complexes engineered to preferentially target proteins containing selenocysteine while avoiding cysteine, achieved by optimizing ligand exchange reactions at the gold(I) center [180]. The results of this investigation are presented in Figure 20.

Figure 21 presents a 3D structure of the TrxR reductase homodimer.

Additionally, the role of labile ligands or leaving groups in metal complexes has been rigorously investigated [181]. Efforts are ongoing to enhance the stability of metal complexes under physiological conditions to discover unique anticancer properties in substitution-inert complexes. The ideal process for discovering new platinum-based drugs should consider three key principles: first, the mechanisms of action and the associated target biomolecules; second, the potential resistance mechanisms of cancer cells and their biochemical pathways; and finally, the pharmacokinetic and toxicity characteristics (ADMET) that will influence the clinical effectiveness of the new drugs [181]. At the conclusion of this rational process, we must design a molecule with a specific structure and set of physical and chemical properties. The structure thus becomes a crucial factor when considering new platinum anticancer compounds. When evaluating the impact of molecular structure on anticancer activity, it is helpful to break down platinum complexes into distinct, important subunits or components of the molecular structure [181]. Therefore, the following structural and electron-dependent factors are essential for comparing platinum complexes: (a) nature of the non-labile ligand or carrier ligand (NLG); (b) nature of the labile ligand or leaving group (LG); (c) oxidation state of the platinum atom; (d) type of atoms (connecting atoms X, Y, Z, W) that link ligands to the platinum atom; (e) characteristics of the axial groups (AG) in platinum(IV) complexes; (f) nuclearity or the number of Pt atoms in the platinum complexes; (g) formal charges present in the molecule; and (h) intrinsic bioactivity of certain ligands or bioactivity induced by molecules attached to ligands through linkers (to achieve a dual mechanism of action or concurrent biological activity) [181]. It is crucial to emphasize that similar coordination complexes from other metal groups in the periodic table do not produce active compounds, or the compounds are too reactive to maintain the necessary relative stability in plasma. However, significant research has been devoted to the synthesis and analysis of complexes of Pd [182,183,184,185], Ru [186,187,188,189,190,191,192,193,194,195,196,197], Au [198,199,200,201,202], Ga [203,204], Rh [205,206], and others. Figure 22 presents the possible mechanism of action of Ru complex and Figure 23 presents the same with regard to the Ga(III) complex.

4. Schiff Base Complexes as Catalysts

Schiff base complexes with transition metals have become highly sought-after co-catalysts due to their accessibility and the versatility of metal centers that can be integrated into the N₂O₂ coordination sphere [206,207]. Their structure allows for a wide range of substituents, enabling chemical flexibility and covalent stability, which is crucial when such catalysts are used on supports [208,209]. Numerous studies have demonstrated that Schiff base metal complexes possess excellent catalytic activity, which can enhance product selectivity and yield in various processes [210,211,212]. The synthesis methods and thermogravimetric stability of these complexes play a key role in their performance as metal catalysts. The applications of metal complexes as catalysts are given in Figure 24.

These complexes, formed from transition metal ions, are effective in both homogeneous and heterogeneous catalytic processes. Their catalytic activity depends on factors like the type of metal ion, ligands, and coordination sites. Schiff bases are particularly useful because they can coordinate a variety of metals at different oxidation states, enhancing the metal ions’ catalytic performance across various reactions [213] (see Figure 25). For example, the catalytic activity of Congo red (CR) in photodecomposition under natural light was assessed using a Co-complex of CX and EBPy, showing a discoloration efficiency of nearly 82% after 80 min of exposure to sunlight [214].

Schiff base complexes with metals like V, Mn, Fe, Co, Ni, Cu, and Zn have also been studied as catalysts for alkene peroxidation reactions, such as those involving limonene, cyclohexene, and styrene [215]. These polymer-supported complexes have shown promising catalytic properties when compared to unsupported catalysts, offering unique advantages in material science and catalysis. The average particle size of the prepared nanofilms, derived from the organic ligand and its chromium(III) complex, were 94 nm and 98 nm, respectively [216]. Optical properties revealed that the direct energy gaps of the nanoparticles (L and M) were 2.6 eV and 3.2 eV, respectively. These results can be attributed to the quantum size effect. X-ray diffraction (XRD) data confirmed the polycrystalline nanostructures of (L and M), with no other phases detected. The efficiency of the fabricated inorganic silicon solar cell (M/Si) was found to be higher than that of the organic solar cell (L/Si).

5. Conclusions

Coordination compounds have demonstrated unparalleled versatility due to their structural diversity and range of applications. The synthesis of these compounds has progressed significantly, incorporating both conventional techniques and innovative approaches to achieve desired properties. Their structural and spectroscopic investigations reveal insights into their reactivity and stability, underpinning their functional potential.

Biologically, coordination compounds stand out for their significant roles as antimicrobial agents, anticancer drugs, and enzyme inhibitors. These properties underscore their potential in therapeutic development and biomedical applications. Beyond biology, their applications in catalysis and advanced material science illustrate their broad utility across various fields.

By bridging fundamental inorganic chemistry with applied sciences, coordination compounds show promise for addressing some of the most pressing global challenges. The continued exploration of novel synthetic methods, coupled with detailed biological and structural evaluations, will pave the way for innovative solutions in healthcare and technology.