Recent trends in medicinal applications of mercury based organometallic and coordination compounds

1 Introduction

Mercury, a natural element, exists in three distinct forms: elemental Hg⁰, inorganic Hg²⁺, and organometallic compounds. ^{1 , 2 , 3} Remarkably, mercury is the only metal that remains in liquid form under surface conditions. In its elemental state, mercury appears as a silvery fluid, distinguished by its heaviness and unique properties. ^{4 , 5 , 6 , 7} Mercury, both in its natural and anthropogenic forms, poses a toxic threat to the environment and living organisms. ^{8 , 9 , 10} Mercury is recognized as one of the most hazardous contaminants due to its ability to accumulate in living tissues, leading to toxicity that affects vital organs such as the kidneys, liver, lungs, and brain. ¹¹ Its stable chemical properties exacerbate its wide-ranging detrimental effects on human health. ^{7 , 12} Mercury(II), known as a soft acid, exhibits high polarizability ¹³ and forms robust covalent bonds with sulfur atoms in cysteine. ^{14 , 15}

While mercury is naturally present in the environment, human activities like coal combustion and mining have significantly increased its mobilization, leading to a threefold or greater rise in mercury levels circulating within surface oceans and the atmosphere. ^{16 , 17 , 18 , 19} Consequently, deposited mercury on land and in water has the potential to undergo transformative processes, fundamentally reshaping the global mercury biogeochemical cycle over extended periods. ^{16 , 20} In aquatic systems, mercury has the capacity to undergo transformation into methylmercury (MeHg), a more hazardous form, primarily through processes such as bioaccumulation. ²¹ Subsequently, individuals are exposed to Methylmercury through the consumption of contaminated seafood. ^{22 , 23}

Schiff base mercury complexes, along with sections derived from cinnamaldehyde, constitute a significant family of Schiff base ligands in coordination chemistry. ²⁴ Due to their appealing electrical, chemical, catalytic, and biological properties, research on inorganic complexes is experiencing rapid expansion. ²⁵ Metal-organic complexes find diverse applications in organic synthesis, serving as catalysts, pigments, dyes, polymer stabilizers, and intermediates. ^{26 , 27} Antimicrobial properties refer to substances that inhibit the growth of microorganisms, while antifungal properties specifically target and combat fungal infections, showcasing potent biological activity against microbial threats. ²⁸ While mercury-based antimicrobials exhibit potent antimicrobial properties, ²⁹ their current usage is restricted due to the significant risk of toxicity in humans. Certain cellular processes cannot be executed by organic molecules ³⁰ alone; however, they can be facilitated by metals, which are essential for the biochemistry of life across all species. ³¹

Mercury, despite its toxicity to humans, holds utility in regulating microbial activities due to its antimicrobial properties. ¹⁰ Mercury toxicity varies with its chemical forms; for instance, organomercurials are more toxic than elemental mercury, while inorganic compounds show lower cytotoxicity. ³² Consequently, these compounds are present in various products such as soaps, detergents, ³³ home cleaners, paints, as well as cookware and utensils used in schools and hospitals. ³⁴ Binuclear mercury complexes of sulfonium ylides, including Schiff bases, have been synthesized, prompting the need to investigate their interaction with DNA ^{35 , 36} for potential chemotherapeutic applications. ^{37 , 38}

Over half a century ago, Nesmeyanov introduced a method to synthesize Hg(II) complexes using phosphonium salts. In 1950, crystallographic analysis confirmed dimeric structures of mercury phosphonium ylides. These complexes exhibit symmetric halide-bridged Hg(II) halides; including bromide, chloride, and iodide. ^{34 , 39 , 40} Mercury can form thione complexes with intriguing structural geometries. Depending on reaction conditions and reactant ratios, mercury can adopt either a monomeric or binuclear form, typically exhibiting a predominantly tetrahedral shape.

2 Mercury complexes with monodentate ligands

Antimicrobial testing has been conducted on mercury complexes containing monodentate ligands labeled from C ₁ to C ₂₁ . ⁴¹ In the example [Hg(L₁)Cl₂], mercury in its zero-oxidation state forms a covalent bond with ligand L ₁ through nitrogen and also binds with two halides. Although its octet appears incomplete, the compound exhibits stability. The antibacterial test with C ₁ was conducted using the in vitro agar diffusion method. ^{42 , 43} The culture suspension of the tested strains was evenly distributed on Muller–Hinton agar medium for the experiment. ^{44 , 45} In the antibacterial test using the in vitro agar diffusion method, each well received a 60 µl solution. C ₁ displayed significant antibacterial activity, with zone diameters of 22, 20, and 20 mm against S. enterica, K. pneumoniae, and Staphylococcus aureus, respectively (Table 1). Moderate activity was observed against M. luteus and Escherichia coli, with zone diameters of 17 mm each. Notably, S. aureus and M. luteus exhibited heightened sensitivity to C ₁ compared to the other tested strains. The Muller-Hinton agar medium facilitated culture suspension distribution. ⁴⁶ The complex [Hg(L₂)_nCl₂(H₂O)₂] comprises water, chloride ions, and ligand L ₂ (Figure 1). C ₂ was tested against bacterial and fungal species, where L ₂ displayed elevated activity against both types of microorganisms. L ₂ , known as vitamin β ₁₃ , is present in cow milk but notably absent in vegetables. Its antimicrobial properties make it effective against various microorganisms, highlighting its significance in microbial control. ⁴⁷ The body’s intestinal flora synthesizes L ₂ , while aspartic acid ⁴⁸ plays a crucial role in pyrimidine nucleotide synthesis. This synthesis pathway underscores the interplay between microbial processes and host metabolism, illustrating the intricate relationship between gut flora and human health. ⁴⁹ It serves as an anticancer agent and facilitates the absorption of vital nutrients like calcium and magnesium. Additionally, it plays a pivotal role in genetic material synthesis, contributing to cellular functions and overall health. ⁵⁰ L ₂ exhibited standard activity against various microorganisms including B. subtilis, E. coli, S. aureus, P. aeruginosa, and C. albicans. In contrast, C ₂ displayed exceptional efficacy, with a concentration of 0.159 μg/mL, notably inhibiting B. subtilis, E. coli, S. aureus, and P. aeruginosa (refer to Table 1). Furthermore, C ₂ demonstrated superior inhibition against C. albicans, with a zone diameter of 27 mm. Compared to other metal (Fe, Co, Ni, Cu, Zn, Cd) complexes of the same ligand, Hg complex C ₂ exhibited enhanced antibacterial and antifungal activity. When compared to the standard drug ciprofloxacin (30 mm), C ₂ displayed slightly lower inhibition (29 mm), indicating comparable effectiveness in inhibiting bacterial and fungal growth at minimum concentrations. ⁵¹ When comparing the results of C ₁ and C ₂ , it’s evident that C ₂ exhibited a higher inhibition effect. This increase in the inhibition zone of C ₂ may be attributed to the bonding of mercury with chloride ions rather than with the sulfur of the ligand. It’s plausible that sulfur could potentially diminish the activity of such complexes against specific strains. The result of the C ₃ complex was tested using the two-fold dilution method. ⁵² At a concentration of 1 × 10³ μg/mL, the effects were compared to those of the common antibiotic chloramphenicol. C ₃ complex expresses the inhibited zone of B. subtilis from 7 ± 2 to 32 ± 4 mm. On Gram-positive bacteria, C ₃ demonstrated strong antibacterial activity, but had no significant effect against Gram-negative bacteria (Table 1). When mixed iodide with ligand, C ₃ showed maximum activity against E. coli and S. aureus. When ligand treated with mercury halides, the activity of C ₃ increased from top to bottom. C ₃ results had a higher inhibition zone against B. subtilis (32 ± 4 mm) than chloramphenicol (24 ± 3 mm). Ligand inhibition diameter is enhanced when combined with mercury. Phosphorus ylides have a wide range of uses as pharmacological and biological active ingredients. Due to their suitability of phosphorus ylides, it is used in industry and chemical preparation. ^{53 , 54} Phosphorus ylides have ambidentate nature and coordinates as a ligand with metals. The main focus of phosphorus ylide is used for deactivation of bacterial growth. ⁵⁵ C ₃ demonstrated the highest potential against B. subtilis 32 ± 2, 30 ± 3 and 32 ± 4 (when mix ligand mix up with HgI₂, HgBr₂ and HgCl₂ respectively). ⁵⁵ The high concentration of the C ₄ complex exhibited higher inhibition growth. As low the concentration of C ₄ activity of inhibition decreased. E. coli displayed the highest activity of 100 mm with 0.227 μg/mL concentration. It showed moderate inhibition at 21.13 mm than S. aureus 11.37 mm at 0.007 μg/mL conc. S. aureus exhibited the higher activity 94.71 mm at 0.227 μg/mL concentration. ⁵⁶ C ₃ complex has a minimum inhibition diameter as to C ₄ . Their diameter may be increased due to small groups attached with mercury. C ₃ contained a bulky group of molecules (Figure 1). Perhaps it may decrease their inhibition zone. A minimum concentration of C ₄ complex used to obtain higher diameter than C ₃ complex. Both C ₅ complex and standard drug separately applied on the strains of the S. aureus, E. coli and C. albicans. Inhibition diameter of C₅ compared with Ampicillin drug. ⁵⁷ Both gave one and the same inhibition diameter (25 and 23 mm E. coli, S. aureus for each) when tested against strains. But fungal strain masked the standard drug Ampicillin activity rather than complex C ₅ . E. coli and C. albicans had equal inhibition zone diameter 25 mm at the same concentration. S. aureus inhibition zone against the complex was 23 mm. ⁵⁸ We compare the inhibition activity of C ₃ –C ₅ complexes (Figure 1). Only C ₄ showed higher activity with minimum concentration. These results determine that C ₄ has a better capability to diffuse into the bacterial cell membrane.

Figure 1:

Chemical activity of complexes C₁–C₅.

C ₆ –C ₉ complexes tested against C. albicans and S. aureus (Figure 2). C ₆ gave responses against S. aureus and P. aeroginosa inhibition zones were 3.7 and 7.5 mm, respectively. C ₇ and C ₉ showed the same inhibition zone with S. aureus and C. albicans. Their inhibition zones are expressed in Table 1. C ₈ –C ₉ compounds showed the same MIC value. But both these complexes have different potential against P. valgerous 9.1, 0.4 mm for each (see in Table 2). C. albicans has a minimum 0.4 mm MIC value. ⁵⁹ C ₈ of minimum concentration 10³ cfu mL⁻¹ was used to test the fungal species C. albicans. C. albicans showed highest inhibition zone with C ₈ . However, their activity slowed down with complex C ₉ . MIC value of fungal increased 9.1–11.8 mm with the C ₈ complex. C ₉ minimizes the MIC value by 0.4 mm. With significantly decreased potency, the time–kill kinetics of the 4 × MIC level was identical to those of the 8 × MIC level. At the 4 MIC level, the initial bacterial kill rate of C ₉ was slower than at the 8 MIC level, necessitating a longer exposure to kill the germs. All the complex antibacterial activity increased due to chelation. ⁶⁰ The metals positive charge is shared partially with the donor atoms, and p electron delocalization may occur throughout the chelate. Metal chelates also make metal chelates more lipophilic, allowing them to pass through the lipid layer of microbial membranes more easily. ⁶¹ Metal-induced oxidative stress has the potential to harm or kill microbial cells. ²⁹ The C ₁₀ showed more activity than the ligand L ₁₀ under similar experimental conditions, which could be due to the fact that chelation significantly reduces the polarity of the metal ion, primarily due to the partial sharing of its positive charge with the donor groups and possible electron delocalization over the entire chelate ring. ⁶² The Schiff base ligands in coordination and inorganic chemistry used as catalyst, molecular fragments and biological modeling. ⁶³ So their good stability and highly solubility in solvent are preferred for complex formation. L ₁₀ only responds with E. coli and P. aeroginosa 5, 8 mm diameter zones respectively. S. aureus and B. subtilis masked the effect of ligands. C ₁₀ increased antibacterial activity of S. aureus from 11 mm. E. coli expressed the inhibition zone 9 mm against C ₁₀ . But B. subtilis had moderate activity against antibacterial agent C ₁₀ . ⁶⁴

Figure 2:

Antimicrobial activity of complexes C₆–C₁₁.

C ₁₁ performance was determined by a well diffusion method. L ₁₁ had shown the minimum inhibition against S. aureus (14–10.5 mm) and P. aeruginosa (13.6–9.5 mm) from higher to lower concentration. The highest activity of the C ₁₁ was observed with chlorine and N₃ molecules. Their activity depends upon the concentration range. The concentration range moves from 15 × 10³ µg/mL⁻¹ to 3.75 × 10³ µg/mL⁻¹ (see Table), inhibition zone also decreases when concentration is low. Chloride C ₁₁ complex showed highest potential against P. aeroginosa. Ligand has the lowest inhibition activity against bacterial and fungal growth. Their activity enhances when combined with mercury halides. Ligand L ₁₁ had lower biological activity than complex C ₁₁ . Complex C ₁₁ has activity higher as compared to the ligand L ₁₁ , only lipid-soluble molecules pass through the cell membrane, making it sensitive and permeable. The lipophilicity of a substance is related to its antibacterial action. The lipophilicity of complexes increases during complexation because the polarity of the metal ion is lowered due to the overlap of its valence orbitals with the ligand orbitals. This component produces-electron delocalization throughout the ligand chelating ring, lowering the positive charge of the metal ion. Their activity is enhanced due to their chelation of the complex with mercury. Hence chelation reduces the polarity of the molecule. Then it enhanced the biological activity. ³¹ As a result, the complexes’ increased lipophilicity facilitates their diffusion into microbial cell walls while also inhibiting active areas of bacterial and fungal enzymes, preventing their growth and ultimately death. The HgL ₁₁ (Cl)₂ and HgL ₁₁ (N₃)₂ azide complexes have been reported to exhibit antibacterial properties in antibacterial experiments.

C ₁₀ –C ₁₁ activities increased due to their chelation. As concentration increased activity also enhanced. The disk diffusion methods were used to test the antibacterial activity of the mercury complexes ⁶³ and its ligand against four bacteria: E. coli and P. aeruginosa are Gram-negative bacteria, and S. aureus and B. subtilis are Gram-positive bacteria. Antibacterial tests revealed that the free ligand and its mercury complexes have good antibacterial action against a variety of microorganisms and that the complex’s antibacterial activity is higher than the free ligand. The mercury chloride and azide complexes had the best efficiency against P. aeruginosa and B. subtilis respectively based on the experimental findings. Except of the mercury thiocyanide complex, all of the complexes showed good efficiency against B. subtilis. S. aureus gave excellent inhibition zone only with mercury bromide and mercury thiocyanate complexes. C. albicans (35.0 mm) show maximum inhibition zone as compared to the A. orayzea (24.4 mm) at same 15 × 10³ μg/mL concentration. Zone of inhibition of C. albicans increased with mercury complexes in following order: HgL ₁₁ (N₃)₂ > HgL ₁₁ Cl₂ > HgL ₁₁ Br₂ > HgL ₁₁ I₂ > HgL ₁₁ (SCN)₂ > L ₁₁ . ³¹ L ₁₂ ligand show higher MIC activity of bacterial and fungal inhibition than C ₁₂ complexes. L ₁₂ gave MIC value at 1.25 mm higher than other bacteria. C. albicans has a higher inhibited zone 12.5 mm with L ₁₂ . As the concentration of ligand increased, the inhibition zone increased from 7.3–12.5 mm. C ₁₂ high rate of inhibition zone (33 mm) observed with (N₃)₂ of C. albicans at 15 × 10³ μg/mL. But their overall activity rate with thiocyanate was maximum (22–31 mm). C. albicans was almost a higher inhibition zone as compared to the bacterial zone diameter. B. subtilis has a higher MIC value 1.25 mm against ligands. But all bacterial strain MIC activity reduces when combined in complex form. B. subtilis and S. aureus showed inhibition zone 21.7 mm and 26 mm respectively at the same 15 × 10³ concentration against [HgL ₁₂ (SCN)₂]. [HgL ₁₂ (N₃)₂] exhibited a maximum response of 14.5 mm against P. aeroginosa. E. coli expressed a 13.5 mm inhibition zone at higher concentration. The antibacterial activity of the produced compounds was compared to those of conventional antibiotics such as Amoxicillin, Penicillin, and Cefalexin. Standard drug Amoxicillin (25 μg/mL) showed B. subtilis (28.10 mm), S. aureus (41.60 mm) and E. coli (20.80 mm). Penicillin (10 µg/disk) expressed B. subtilis (30.50 mm), S. aureus (47.40 mm) and E. coli (9.70 mm). Cefalexin (30 µg/disk) exhibited B. subtilis (37.60 mm), S. aureus (41.60 mm) and E. coli (22.56 mm). ⁶⁵ C ₁₃ exposed different antibacterial activity as concentration increased. L ₁₃ at 100 μg/mL concentration gave higher inhibited zone of B. subtilis than other bacterial strains. C ₁₃ increased bacterial inhibition of B. subtilis at 100 μg/mL concentration 40.50 mm. But lower inhibition zone observed of P. aeroginosa of 16.74 mm than B. subtilis, S. aureus and E. coli. ⁶⁶ L ₁₁ was higher inhibition zone than L ₁₂ . Because L ₁₁ –L ₁₂ ligands only having difference due to methyl group. L ₁₁ was not obtained CH₃ group (Figure 2). Alkyl group masked the activity. When compare the inhibition diameter of the complexes C ₁₁ –C ₁₂ . C ₁₁ was higher activity. Hence it is clear that when complex contain bulky alkyl their activity reduces (Figure 2). C ₁₃ complex was higher inhibition diameter than C ₁₁ and C ₁₂ . Because complex C₁₃ has two bonded Hg atoms. The inhibitory approach was used to investigate the biological activity of the ligand and their complexes. ⁶⁵

The ligand and its complexes are highly effective in inhibiting the spread of germs at the concentrations used. L ₁₄ potential observed against Gram positive and negative bacterial strains. It only revealed the inhibition zone of S. aureus and E. coli 6 mm and 5 mm respectively. C ₁₄ complex showed the highest antibacterial response against bacterial growth. C ₁₄ expresses the 31 mm inhibition zone of S. aureus. C ₁₄ inhibition zone was increased against E. coli bacteria. This response determined that activity of ligands increased when coordinated with mercury. ⁶⁷ C ₁₅ displayed the highest MIC value of A. niger of 50 μg/mL. C ₁₅ was affected highly on the fungal specie A. niger and P. notatum. Both showed 50 mm inhibitory diameter. It also gave response against K. pneumonia, S. aureus and B. subtilis, observed moderate behavior of 25 μg/mL for each species. It is highly affected by the E. coli strain. E. coli exhibited the same inhibition zone as the fungal species (50 mm). The MIC value of E. coli bacterial strain compare with standard drug streptomycin. Streptomycin MIC value (6.25 mm) was very small as compared to the bacterial strain (50 mm). But fungal activity compared with Ketoconazole (standard drug). The Ketoconazole (3.125 mm) tested result was much smaller than mercury complexes. C ₁₅ showed an excellent inhibition zone as compared to the standard drug treatment. ⁶⁸ C ₁₆ complex showed higher IZD value than MIC. Gram-negative bacteria were shown to be more vulnerable towards amino pyridine derivative in term of toxicity (IZD 11–13 mm) than Gram-positive bacteria (IZD 58 mm) in the tests. C ₁₆ on the other hand, was discovered to be more effective against bacteria than pyridine dicarboxylic acid derivatives (Figure 3). C ₁₆ complex disclosed highest potential against S. aureus. C ₁₆ has a greater ability to inhibit the growth of bacteria. C ₁₆ increased inhibition growth of E. coli, S. pyogenes, S. epidermidis and P. aeroginosa 128 mm MIC values of all species. C ₁₆ tests with P. vulgaris express moderate inhibition than other bacterial species. S. aureus shows minimum inhibition (32 mm) response against mercury complexes. But C ₁₆ showed the highest IZD value against S. aureus and S. epidermidis growth. Because of the partial sharing of the metal ion’s positive charge with the donor groups and the possibility of electron delocalization over the chelate ring, chelation can diminish the polarity of the metal ion. The lipophilic property of the central metal ion is amplified in this position, resulting in a desire for penetration through the lipid layer of the cell membrane. Increased lipophilicity improves the C ₁₆ complex (Figure 3), and entry into lipid membranes while also blocking metal-binding sites in microorganism enzymes. Complex C ₁₆ has a minimum difference with other complex inhibition tests. But the standard drug Gentamicin had a maximum inhibition effect compared with C ₁₆ . Gentamicin has higher potential against E. coli 31 mm IZD value. It also inhibited the activity of S. epidermdis and S. pyogenes 28 mm and 21 mm respectively. ³² In comparison C ₁₄ has a higher effect on bacterial strain than C ₁₆ .

Figure 3:

Chemical activity of monodentate ligands complexes C₁₂–C₁₆.

Their activity is enhanced due to coordination and chelation of the complex. Due to variations in cell wall construction, the growth inhibition zone values show that they have moderate action against P. aeruginosa with MIC values of 500 mm and are inactive against E. coli (Table 2). Cup-plate agar and microdilution method ⁶⁹ was used for testing the bacterial strain inhibition zone. Ligand L ₁₇ exhibited higher inhibition than C ₁₇ (Figure 4). C ₁₇ showed the highest potent against bacterial growth when a small crystal size used for the test. C ₁₇ had shown the highest inhibition of B. subtilis of 30 mm. S. aureus exposed the 14 mm inhibition zone growth with C ₁₇ . But E. coli masked the effect of complex. Complex increased MIC value of 500 mm of P. aeroginosa and S. aureus. B. subtilis and B. cereus had lowest MIC value 2.79 and 1.95 mm both L ₁₇ and their complex respectively. S. aureus increased MIC value of 500 mm. Standard drug gentamicin inhibition is higher with Gram negative bacteria as compared to the C ₁₇ . P. aeruginosa, E. coli, S. aureus, and B. cereus exhibited 20 mm inhibition zones for each. B. subtilis expressed the 23 mm inhibition zone against gentamicin. But their MIC value was very small, B. subtilis and B. cereus showed higher inhibition with complex as compared to the standard drug gentamicin. L ₁₇ was found to have better action against P. aeruginosa and S. aureus than the prepared complex C ₁₇ . It can be claimed that altering the phosphoryl group substituents and the electrostatic interactions between ions pairs (likely leads to increased activity. L ₁₇ smaller crystallite size could also explain why it has a higher affinity for the named bacterium than C ₁₇ . ^{56 , 70} C ₁₈ –C ₁₉ expressed the different bacterial activity due to variation in concentration. Agar-gel diffusion and Mueller–Hinton broth were used to determine the sensitivity of the bacterial strains. C ₁₈ gave better result at 4 μg/mL concentration than C ₁₉ used of 10 μg/mL. C ₁₈ showed the inhibition zone from 30–35 mm of S. aureus. C ₁₈ inhibited zone of P. valgaris was 25–28 mm at 4 μg/mL concentration. It shows excellent activity with B. cereus 44–50 mm. C ₁₉ at 10 μg/mL concentration inhibited bacterial zone 11 mm for each of B. cereus and S. aureus. B. cereus inhibition zone compared with standard drugs chloramphenicol, Tobramycin and Tetracycline at 1 × 103 μg/mL concentration. Tobramycin (15 mm) and Tetracycline (17 mm) inhibited the growth of B. cereus than chloramphenicol. B. cereus masked the effect of chloramphenicol. The antibacterial activity of this Hg(II) complex (C ₁₉ ) with phosphonium ylide ligand is far superior to that of mono and bidentate metal complexes of phosphine and sulphur ylides. ³⁴ Bulky group reduced the metal activity (Figure 4). So the C ₁₈ complex exhibited higher activity than C ₁₉ . Their activity may increase due to the presence of NO group. C ₂₀ and L ₂₀ show different behavior against bacterial and fungal strain. C ₂₀ shows a higher inhibition zone than L ₂₀ because the complex contains copper, mercury and halogen salt. Greater inhibition effect was observed in E. coli due to C ₂₀ . Maximum difference present between ligand and complex against E. coli (13.1–25.3 mm). But fungal species masked the effect of complex. In this case observe that only C. albicans is affected by ligands. If comparing the inhibition effect Cu-salt, Hg-salt with complex according to the data, salts have greater ability to disturb the bacterial and fungal strain. Less inhibit activity of complex shows that have less capability to incorporate into the bacterial and fungal strain. ⁷¹ C ₂₁ and L ₂₁ have large differences due to their inhibitory effect. C ₂₁ showed a marked inhibition zone. Complex had the same inhibition zone E. coli and S. aureus (23.3 ± 0.6 mm). But S. mutans (44.3 ± 0.6 mm) showed maximum inhibition. As compared to complex ligands, it has minimal effect on microbial strain. It was observed that large inhibitory zones due to increase the number of hydrogen bonding. It may be less polarizability of C ₂₁ means it reduced the ability to form higher number of hydrogen bonds which leads to its minimal impact on microbial strains compared to complex ligands. These effects enhance the penetration of the complex into microbial strain (Figure 5). ⁷²

Figure 4:

Antimicrobial activity of monodentate ligands complexes C₁₇–C₂₀.

3 Mercury complexes of bidentate ligands

Bidentate ligands vary from (C ₂₂ –C ₂₇ ). Dithiocarbamate is an organic compound with different oxidation states used in material sciences and for the formation of transition metal complexes. Dithiocarbamate is used in agriculture, medicine, clinical and industrial applications. ⁷³ Muller Hinton method was utilized for testing the sensitivity of bacteria with 1 × 10³ μg/mL concentration of C ₂₂ and L ₂₂ . However, the Potato Dextrose Agar method used for fungi with 10 μg/mL complex and ligand concentration. S. aureus and E. coli showed highest activity with L ₂₂ (b). L ₂₂ (b) E. coli and S. aureus showed same inhibition 4.0 mm for both. But L ₂₂ (a) had different response against both E. coli and S. aureus 3.9 mm and 3.2 mm respectively. Fungi behave as moderate with L ₂₂ (a) but do not show any response with L ₂₂ (b). C ₂₂ gave minimum potent against E. coli and S. aureus 1.1 and 1.9 mm respectively as compared to the other metal complexes with the same ligands. Albicans (fungi) mask the effect of C ₂₂ . But L ₂₂ (a) exposed the activity against T. viride and M. albicans with 2.5 and 3.0 mm inhibition zones. MIC value of E. coli and S. aureus are 0.25 mm with both (a) and (b) ligands. But their potential was increased against fungi with (a). No activity with (b). E. coli gave a 1.0 mm MIC value with C ₂₂ . C ₂₂ have minimum MIC with S. aureus 0.25 mm. Fungi express excellent MIC value with L ₂₂ as compared to the bacterial strains. ⁷⁴ The disk diffusion approach method was used to determine the sensitivity of the bacterial and fungal strains. C ₂₃ attain the noble gas electronic configuration. L ₂₃ (a) and (b) inhibited the growth of S. aureus but E. coli masks the effect of both ligands. L ₂₃ (a) displayed the highest diameter zone of inhibition of S. aureus 16 mm. But L ₂₃ (b) express lower inhibition zone of S. aureus 11 mm. C ₂₃ increase diameter zone of S. aureus than E. coli. S. aureus inhibited zone observed of 21 mm. Inhibition zones of C. tropicalis and C. albicans were 16 mm and 15 mm respectively. C ₂₃ lower inhibition zone of 14 mm of E. coli. Complex [Hg₂(L ₂₃ a)(L ₂₃ b)(H₂O)₄]Cl₂ was an excellent inhibition zone as compared to the other metal complex with the same ligand. ^{75 , 76} When comparing the results C ₂₂ ha a lower inhibition effect than C ₂₃ . Their activity improved due to chelation with mercury. Does not matter what types of molecules are attached with mercury. Coordinate bonding of ligands with mercury enhances the inhibition zone of strains.

Figure 5:

Chemical activity of ligand complex C₂₁.

C ₂₄ showed a higher inhibited zone of S. aureus of 21 mm. E. coli inhibited zone is 19 mm with C ₂₄ . C ₂₄ lower inhibited zone observe with P. valgaris (15 mm). MIC value of C ₂₄ higher with P. aeroginosa, S. pyogenes, S. epidermidis and P. valgaris is 64 mm for each strain (Table 2). Their lower MIC value is determined with S. aureus 16 mm. MIC values ranged from 16 to 256 mm, with IZD values ranging from 4 to 21 mm in most cases. The same MIC was observed with P. aeruginosa, P. vulgaris, S. pyogenes and S. epidermidis 64 mm. E. coli expresses the 32 mm minimum inhibitory concentration against complex. Compared to their organic constituents, both complexes had the lowest MIC value and the highest IZD. ³² Antipyrine’s amino group as a chelation site exhibit emphasizing activity with transition metal ions via covalent or coordination interactions. L ₂₅ provided a higher inhibition zone 11 mm with Bacillus than other strains. S. aureus, E. coli and Pseudomonas inhibited zone of 6, 7 and 9 respectively. The observation of C ₂₅ potent against Bacillus is 19 mm higher than other bacterial strains. Pseudomonas expressed moderate behavior (10 mm) with the effect of C ₂₅ . The inhibition diameter of S. aureus and E. coli was 15 and 12 mm respectively for each strain with C ₂₅ . ⁷⁷ 8-Hydroxylquinoline is used in agriculture to kill microorganisms. ⁷⁸ Ligand and C ₂₆ were tested with bacterial strains. S. aureus expressed higher inhibition with ligand. Their activity is due to the hydroxyl attached to the ligand. S. aureus tested activity against ligand were 34 mm. P. aeruginosa was showed the 27 mm inhibition zone. Bacillus was lowest diameter zone about 21 mm. But Providencia mask the effect of ligand. When C ₂₆ was tested against bacterial strains Bacillus showed the highest response. Their inhibition zone was 30 mm due to the C ₂₆ complex. S. aureus also revealed the inhibited zone almost 21 mm. Providencia and P. aeroginosa had moderate inhibition zone 12 and 18 mm respectively. There is a small difference of inhibition about the other metal (Zn, Cu etc.) with the same ligand complexes. Except for Providencia, a comparison of ligands and their metal complexes revealed that free ligands (8-HQ) had lower antibacterial activity than their complexes, while Schiff had higher activity. Except for [HgL ₂₆ (8-HQ)₂], which had a mild effect, all complexes had a detrimental effect on Providencia development. The [HgL ₂₆ (8-HQ)₂] complex had a beneficial effect in term of their improved antibacterial activity on four organisms (Staphylococcus aureus, Bacillus, Pseudomonas aeruginosa, and Providencia) with moderate to high activity and an inhibitory zone of 12–30 mm. C ₂₅ –C ₂₆ was compared in term of their inhibited activity (Figure 6). C ₂₆ bared the highest inhibition zone because it contain hydroxyl group than C ₂₅ . ⁷⁹ Both the complexes such as C ₂₅ and C ₂₆ complete the octet to attain noble gas configuration. Chelating agents enhance the activity of complexes. Tweedy’s theory of chelation, which shares the positive charge of the metal ion with donor groups and decreases its polarity via overlapping ligand orbitals, explains why metal complexes exhibit improved inhibitory action. Ligand and metal (mercury) combinations have diverse effects on antimicrobial and antifungal activity. It makes the complexes stable. C₂₆ complex has different inhibition zone with different concentrations. L ₂₇ shows less effect on C. albicans inhibition zone (10.6 mm) at higher concentration of sample. HgL(SCN)₂ shows maximum polarity to damage the fungi cell (27.7 mm). Other chelating complexes have moderate effect but greater than ligands. HgLCl₂ and HgLBr₂ show dynamic activity as the concentration of the sample increases. C ₂₇ has a marked effect on bacteria. It has a large effect on S. aureus and B. subtilis (35.7 and 26.5 mm) respectively. This effect is enhanced with increasing concentration of the iodine complex. L ₂₇ shows no inhibition zone at lowest concentration without P. aeruginosa. As the contraction of the complex increases, large effects are observed in bacterial strain. All the halogens containing complexes show minimum MIC value. L ₂₇ and HgL(NO₃)₂ show good MIC value S. aureus and P. aeroginosa 1,250 μg/mL but HgL(NO₃)₂ has average activity against P. aeroginosa. E. coli has a large effect due to HgL(N₃)₂ and HgL(SCN)₂ 2,500, 5,000 μg/mL MIC value respectively of these complex samples. ⁸⁰

Figure 6:

Antimicrobial activity of bidentate ligands complexes of C₂₂–C₂₄.

4 Mixing ligand complexes

Mixing ligand complexes contain small numbers of (C ₂₈ –C ₃₉ ). C ₂₈ was used to test the bacterial and fungal growth. But only fungi showed a response against C ₂₈ and C ₃₀ . C ₂₈ has the highest inhibition MIC value of C. albicans 42.9 mm at concentration of 0.1 μg/mL. But C ₃₀ had shown a minimum 11.8 mm response against C. albicans. MRSA had excellent MIC activity against C ₂₈ about greater than 42.9 mm but very small response showed against C ₃₀ . Bulky groups cause steric hindrance. Hence activity of the C ₃₀ was reduced against bacterial and fungal species. So C ₂₈ antifungal activity against fungi activity was higher than C ₃₀ . Standard drug TCN and TBF used to determine the activity of microbes. Only TCN inhibited the MRSA growth about 12 mm diameter. C. albicans hides the potential of the TCN. TBF only inhibited the minimum 5 mm growth of C. albicans. ²⁹ C ₂₉ complex tests apply different concentrations on bacterial growth disks. As the concentration increased from 5 to 40 μg/mL their inhibition increased. S. aureus (12 mm) and P. aeroginosa (14 mm) show an inhibition zone against L ₂₉ a. But L ₂₉ b not only inhibits the growth of S. aureus and P. aeroginosa but also inhibits the B. subtilis activity. Other strains such as B. subtilis, E. coli and C. albicans masked the effect of the L ₂₉ a. Higher inhibition growth was observed from with chlorine molecules other than halide molecules. S. aureus demonstrates the highest diameter zone 19–25 mm at concentration of 5–40 μg/mL than other bacterial species. E. coli displayed a minimum inhibition zone range of about 10–25 mm at concentrations of 5–40 μg/mL. C ₂₉ I ₂ shows a moderate response against bacteria. Their highest response was observed against B. subtilis of 15–17 mm and lowest activity with E. coli was 7–14 mm. But the complex C ₂₉ has less inhibition zone as compared to mercury halides. E. coli, B. subtilis, S. aureus and P. aeroginosa growth inhibition was 9–11 mm, 13–18 mm, 14–19 mm and 12–16 mm respectively. Standard drug Cefixime (5 µg/disk concentration) inhibits the growth of B. subtilis (9 mm) and E. coli (20 mm). There is no effect on S. aureus and P. aeroginosa. But C ₂₉ inhibits the growth of all tested strains. Penicillin showed excellent effect against S. aureus (26 mm) as compared to C ₂₉ (19 mm). Streptomycin also showed high activity 22 mm at minimum 10 µg concentration as compared to the C ₂₉ 19 mm (4 × 10⁴ µg/mL). ⁸¹ C ₃₁ and ligand used to perform the test against bacterial and fungal growth. Only S. aureus and C. albicans express positive behavior against ligands. All tested bacterial and fungal specie were acceptable responses against C ₃₁ . S. aureus had the highest inhibition zone than other strains. Their diameter zone approximately 20 mm was observed. B. subtilis showed in a 17 mm inhibited zone. P. aeroginosa, C. albicans and E. coli were moderate 8 mm for each strain activity against C ₃₁ ⁸² (Figure 7).

Figure 7:

Chemical activity of complexes C₂₅–C₂₇.

The inhibition zone of C ₃₂ was highest as compared to C ₃₃ . Due to Hg attached with different halide molecules and phenyl groups. Both complexes C ₃₂ and C ₃₃ showed MIC activity greater than 0.5 mm at lower concentration of 0.5 × 10³ μg/mL. These complexes determined the S. aureus and E. coli MIC activity. This structure is hydrophobic (lipophilic), limiting chemical compound transport toward the cell cytoplasm and membrane. ^{83 , 84} Both C ₃₂ and C ₃₃ were more sensitive to E. coli than P. aeruginosa. The distinction between these two Gram-negative organisms stems from their porin architecture. E. coli’s porin design includes bigger, more permeable channels (like OmpF and OmpC), which promote antibiotic susceptibility and broad molecule passage. On the other hand, porins from P. aeruginosa, such as OprF and OprD, have smaller channels that restrict the movement of particular molecules, promoting resistance to antibiotics and environmental adaption. Their unique physiological mechanisms and pathogenic potentials are highlighted by these characteristics. Another method of antibacterial activity of these compounds is cell wall inhibition. ^{85 , 86} As a result, Gram-positive species with multilayer peptidoglycan in their cell walls ⁸⁷ have been more sensitive to these compounds. The presence of Hg in the structures of C ₃₂ and C ₃₃ may cause them to target mostly bacterial enzymes, peptidoglycan synthesis and metabolic enzymes. As a result, in the presence of C ₃₂ and C ₃₃ most of the active enzymes of the bacterial cell will be inactivated, resulting in disturbing the bacterial cell growth and causing death of bacteria. Maximum inhibition showed B. subtilis from 18 to 23 mm as concentration increased. E. coli showed greater response with C ₃₃ as compared to the C ₃₂ . Their activity increased from 11–19 mm as concentration increased. S. aureus activity improved from 16–22 mm. Their activity enhanced as concentration of the complexes increased. P. aeroginosa expressed lower inhibition 7–14 mm than remaining tested strains. Complex C ₃₂ has greater response due to maximum mercury atoms attached in circular form. Hence it is clear that C ₃₂ is better as compared to C ₃₃ due to their number of mercury metals attached. ^{88 , 89} C ₃₄ gave a higher inhibition zone when tested for E. coli with 5 μg/mL concentration. The inhibition zone was 33 mm. S. aureus showed maximum 27 mm inhibition zone at 5 μg/mL concentration. Their minimum inhibited zone at 10 μg/mL concentration. P. aeroginosa was no activity expressed with C ₃₄ . But E. coli showed maximum response with 10 μg/mL concentration as compared to other species. P. aeroginosa gave minimum inhibition zone 21 mm as compared to other specie at 5 μg/mL. p-chloro, p-bromo and p-hydroxyl complex of C ₃₄ (Figure 9) showed higher value 8 mm of inhibited of E. coli diameter at the concentration of 100 μg/mL. But Z. mobilis increased inhibited zone from 8 to 10 mm. p-bromo and hydroxyl at lower concentration 25 μg/mL was 6 mm inhibited zone against Z. mobilis. ⁹⁰ C ₃₅ showed maximum inhibited zone against E. coli and Z. mobilis at maximum concentration. Benzene attached C ₃₅ complex was lowest inhibition than other attached alkyl groups. C ₃₅ used potent antifungal activity. A. niger was maximum inhibition zone 9–15 mm. But Cerveleria showed maximum inhibition zone 6–12 mm. C ₃₅ showed best antifungal activity as compared to the antibacterial. Their activity also enhanced if alkyl group attached at para and ortho position than Meta position. If we compared the results of bacterial specie to determine inhibition zone Z. mobilis > E. coli. ⁹¹ In C ₃₅ alkyl group decreased their activity. Both complexes contain sulphur, chloride and amine groups. But alkyl group reduced the activity of C ₃₅ . C ₃₄ enhanced the antibacterial inhibition effect. C ₃₆ MIC can be calculated using the disc diffusion approach, which involves preparing discs containing 1.9–1,000 g/mL of ampicillin testing them against the bacteria listed above. Two dilutions of the solution was prepared. ⁹² The microbe suspensions were introduced to the matched wells at a concentration of 10 CFU/mL (colony forming unit/mL). ^{93 , 94} The dishes were incubated for 24 h at 36 °C. L ₃₆ showed the maximum behavior of S. aureus, E. coli and C. albicans. C ₃₆ showed moderate activity as compared to the L ₃₆ . Ligand showed the highest of about 21 mm of C. albicans. S. aureus expressed a maximum 19 mm response than E. coli (11 mm). C ₃₆ complex increased inhibition of C. albicans 14 mm than other S. aureus and E. coli. For determination of MIC activity used two fold dilution methods. The MIC value of C ₃₆ complex enhances the inhibition rate of E. coli of 500 mm. S. aureus exhibits a 250 mm inhibitory zone. C. albicans was a medium MIC effect against the C ₃₆ complex. Compare the inhibitory zone of Ampicillin with C ₃₆ . It showed higher activity with E. coli (25 mm) and S. aureus (24 mm) as compared to the C ₃₆ . But their MIC value is less than C ₃₆ . E. coli exhibited 125 mm MIC activity but S. aureus showed 93.7 mm. C. albicans hides the effect of standard drug Ampicillin ⁹⁵ C ₃₇ complex tested with bacterial and fungal species. Their maximum inhibition activity was observed with C. albicans. Their minimum results with S. aureus and P. aeroginosa use the same concentration at all species. L ₃₇ expresses higher inhibition with P. aeroginosa 256 mm diameter. C. albicans showed 128 mm inhibition diameter. But L ₃₇ minimum results with S. aureus. S. aureus 64 mm inhibition was observed. C. albicans and C. parapsilosis had excellent inhibitory activity with C ₃₇ . C. parapsilosis had the same inhibitory value with ligands and complex 256 mm. But E. coli and S. aureus show minimum activity with C ₃₇ . The standard drug was only excellent activity against E. coli (64 mm). ⁹⁶ C ₃₈ complex applied on the bacterial strains. Only S. aureus exhibit a higher MIC 25 mm value. P. valgerous showed 35 mm MIC value. Three bacterial strains such as B. subtilis, S. aureus and E. coli were minimum MIC values respectively 25, 20 and 20 mm. S. aureus showed a higher 8.5 mm inhibited zone. Their inhibition was higher as compared to other species treated with complex C ₃₈ . B. subtilis and P. vulgaris exhibited maximum inhibition of 7.6 and 6.9 mm respectively. The remaining strains observed diameter 4.1, 3.1 and 2.5 mm respectively E. aerogenes, S. enterica and E. coli. The complex has higher MIC values as compared to the inhibition zones of bacterial strain. Bacterial cell membranes serve as a strong barrier against biocidal drugs. ⁹⁷ The analysis for membrane damage demonstrated the complexes’ capacity to compromise membrane integrity, so validating the antibacterial activity which has been reported. This emphasizes how these complexes work against these bacteria. The complex, ligand, and metal salt were tested for antibacterial activity against Gram-positive and Gram-negative microorganisms, including S. aureus and E. coli. C ₃₉ gave higher inhibition diameter with E. coli approximately 3.8 mm. S. aureus express 2.6 mm inhibition diameter. E. coli exhibited higher diameter of 5 mm after being treated with ligand. But E. coli showed a high inhibition zone 2.8 mm as compared to their ligand. Mercury salt potential was higher as compared to the complex. Hg salt potential against E. coli was 4.4 mm and 4 mm for S. aureus. In addition, each compound’s antibacterial activities are greater of E. coli than S. aureus. ⁹⁸ C ₃₉ contained two benzyl groups but C ₃₇ and C ₃₈ 1, 1 benzyl group. Both C ₃₇ –C ₃₈ have an extra sulphur group (Figure 8). It may be sulphur group and chloride improved complex activity. C ₃₉ does not contain a sulphur group.

Figure 8:

Chemical activity of mixing ligands complexes C₂₈–C₃₃.

Figure 9:

Antimicrobial activity of complexes C₃₄–C₃₉.

5 Conclusions

As a result of the data reviewed in this context, it is important to note that numerous mercury complexes have demonstrated excellent antimicrobial efficiency, indicating that they could be useful with new compounds. Hg activity reduced may be due to their ligands and functional molecules such as CH₃, CO and alkyl groups combining in complexes with mercury. Mercury complexes activities enhanced when combined with ligands through chelation rather than direct bonding. Functional groups such as NO, OH, Cl and S enlarge these complexes activity. Hg complexes have moderate activity as compared to the other metal complexes. This could point researchers in the path of more targeted success with metal-based medicines anti potential agents in the service of humanity. Ligands and other groups linked through coordinate bond enhance the mercury complexes activity. Their test clearly shows that activity does not depend on how much the larger complex is used. It only depends on reactivity of the compound and their combination of the metal.