Abstract (English):
Introduction. Infectious diseases remain a serious threat to humanity worldwide as bacterial pathogens grow more diverse. Bacteria, fungi, and parasites develop resistance to clinically approved antimicrobials, which reduces the efficacy of available drugs and treatment measures. As a result, there is an ever growing demand for new highly effective pharmaceuticals. This review describes mono- and polynuclear platinum and palladium complexes with antimicrobial properties. We compared several groups of antibacterial agents: antibiotics, antioxidant biologically active substances, antimicrobial nanoparticles, nanocomposite materials, biopolymers, micellar systems, and plant extracts. Study objects and methods. The review covered relevant articles published in Web of Science, Scopus, and Russian Science Citation Index for the last decade. The list of descriptors included such terms as mononuclear and binuclear complexes of platinum, palladium, and antimicrobial activity. Results and discussion. Chelates of platinum, palladium, silver, iridium, rhodium, ruthenium, cobalt, and nickel are popular therapeutic agents. Their antimicrobial activity against pathogenic microorganisms can be enhanced by increasing their bioavailability. Metalbased drugs facilitate the transport of organic ligands towards the bacterial cell. The nature of the ligand and its coordination change the thermodynamic stability, kinetic lability, and lipophilic properties of the complex, as well as the reactivity of the central atom. Polynuclear platinum and palladium complexes contain two or more bound metal (coordinate) centers. Covalent bonding with bacterial DNA enables them to form a type of DNA adducts, which is completely different from that of mononuclear complexes. Conclusion. Metal-based drugs with functional monodentate ligands exhibit a greater antimicrobial effect compared to free ligands. Poly- and heteronuclear complexes can increase the number of active centers that block the action of bacterial cells. When combined with other antibacterial agents, they provide a synergistic effect, which makes them a promising subject of further research.

Keywords:
Antimicrobial activity, antibacterial activity, antitumor activity, mononuclear complexes, polynuclear complexes, platinum (II), palladium (II), platinum (IV)

INTRODUCTION
Infectious diseases represent a serious problem
worldwide. The growing antimicrobial resistance of
various pathogens reduces the efficacy of existing
drugs and preventive treatment, thus fuelling the neverending
search for new drugs. Living organisms are
in constant contact with a huge number of chemical
compounds. Some of them are beneficial, e.g. proteins,
lipids, carbohydrates, biologically active substances,
mineral components, etc., while others are toxic. People
in industrial regions are especially vulnerable to the
negative impact of xenobiotics.
The antioxidative system of living organisms
consists of the enzymes of oxidismutase, peroxidase,
and catalase. It helps to destroy bacteria and substances
absorbed by leukocyte cells. Antioxidants provide
protection against the damage that results from the
controlled production of reactive oxygen intermediates
followed by lipid peroxidation, protein damage, and
DNA rupture. Thus, antioxidants reduce the risk of
chronic diseases, including cancer and heart diseases.
Enzymes and oxygen are responsible for regulated
oxygenase and dioxigenase oxidation of biosubstrates
in the organism. Biosubstrate comes in direct contact
with oxygen only in the presence of enzymes. Therefore,
oxidation processes can be controlled. In case of
direct contact of the substrate with reactive oxygen
intermediates, the redox process proceeds according

to the radical mechanism, and its rate depends on the
concentration of free radicals in the cell.
Radiation exposure causes violation of the redox
transformations of complexing ions in various biological
complexes. Various radicals and other reactive oxygen
intermediates form as a result of the activation and
decomposition of water molecules.
Induced cytochrome enzyme system ensures the
oxidative transformation of xenobiotics. It triggers
the activation mechanism of the genes responsible for
protein synthesis. Transcription of the corresponding
part of the chromosome starts when the xenobiotic
binds to the receptor protein in the cell. The
resulting mRNA leaves the nucleus and becomes the
template for the synthesis of the protein component
of the monooxygenase. Drugs, polycyclic aromatic
hydrocarbons, food components, e.g. flavonoids,
xanthines, and indole derivatives, can exhibit
monooxygenase-inducing properties. The intake of
xenobiotics increases the number of monooxygenases,
which leads to immunological exhaustion [1].
This review features mono- and polynuclear
platinum and palladium complexes with antimicrobial
properties. It contains a comparative analysis of
various classes of antibacterial agents, e.g. antibiotics,
antioxidant biologically active substances, antimicrobial
nanoparticles, nanocomposite materials, biopolymers,
micellar systems, and plant extracts.
STUDY OBJECTS AND METHODS
The review presents platinum and palladium
complexes with antibacterial properties, various
coordination structure, and different methods of ligand
coordination. The list included mono- and polynuclear
complexes with the central atom oxidation state of (+2)
and (+4). The polynuclear complexes contained both
mono- and polydentate bridging and terminal ligands.
For comparison, we examined the main antibacterial
agents – antibiotics, antioxidant biologically active
substances, antimicrobial nanoparticles, and nanocomposite
materials, as well as such biopolymers as
polysaccharides, peptides, micellar systems, and plant
extracts.
The review was based on highly relevant and recent
publications retrieved from the Web of Science, Scopus,
and Russian Science Citation Index bases. We limited
the search to mononuclear and binuclear complexes of
platinum and palladium and antimicrobial activity.
RESULTS AND DISCUSSION
Antibiotics. Antibiotics are natural substances of
microbial, plant, and animal origin and products of their
chemical modification that are capable of suppressing
the growth of bacteria, lower fungi, protozoa, viruses,
or cancer cells, when administered in low concentrations
(10–3–10–2 μg/mL). Science knows several thousands
of natural antibiotics, and almost all of them are
heterocyclic compounds. Synthetic and semi-synthetic
antibiotics are more active and stable than natural ones.
Antibiotics can be divided into four main types
according to the mechanism of action: 1) those that
inhibit the synthesis of bacterial cell walls; 2) those that
inhibit template (ribosomal) protein synthesis; 3) those
that inhibit nucleic acid synthesis; 4) those that inhibit
the functioning of the cytoplasmic membrane (Fig. 1).
Antibiotics, antiseptics, bacteriophages, disinfectants,
preservatives, and other antimicrobials are used in all
industries. However, large doses of antibiotics and long
treatment sessions may cause allergic or direct toxic
reactions that affect kidneys, liver, gastrointestinal tract,
central nervous and hematopoietic systems, etc.
The European system for surveillance and control
of antimicrobial resistance has identified seven
types of clinically significant bacteria that shape the
antimicrobial resistance in Europe: Streptococcus
pneumoniae, Staphylococcus aureus, Escherichia coli,
Enterococcus faecalis, Enterococcus faecium, Klebsiella
pneumoniae, and Pseudomonas aeruginosa.
Figure 1 Antibiotics: mode of action
Folic Acid Metabolism
Trimethoprim
Sulfonamides
Sulfones
Cell wall synthesis
Cycloserine
Bacitracin
ß-lactams
glycopeptides
p-aminobenzoik acid
Cell membrane
Polymyxins
Folinic acid
Protein synthesis
Aminoglycosides
Macrolides
Lincosamides
Streptogramins
Amphenicol
Tetracyclines
Rupirocin
DNA-dependent
RNA polymerase
Rifamycins
DNA replication
Quinolones
DNA Nitroimidazoles
mRNA
Folic acid
Ribosomes
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Strains of microorganisms isolated from various
plant and animal raw materials demonstrate antibacterial
properties, e.g. Bacillus safensis, Bacillus endopheticus,
and Bacillus subtilis [2]. Bacteriocins of lactic acid
bacteria strains of Lactobacillus delbrueckii B2455,
Lactobacillus paracasei B2430, and Lactobacillus
plantarum B884 are known to possess an antimicrobial
potential [3].
As a rule, antimicrobial activity is determined by
the optical density of culture fluid by using the method
of serial dilutions, as well as the disk-diffusion method
or diffusion E-test. The list of quantitative indicators
that describe antibacterial activity includes: minimum
inhibitory concentration (MIC); minimal inhibitory
concentrations that inhibit 50% and 90% of bacteria
(MIC50 a nd M IC90, respectively); minimal bactericidal
concentration that causes the complete death of bacterial
cells (MBC).
Antioxidant biologically active substances.
Scientists pay much attention to the antioxidant activity
of organic and organometallic compounds against toxic
active forms of oxygen and nitrogen. Antioxidants
prevent oxidative reactions by stabilizing free radicals.
However, the necessary amount of antioxidants can
be obtained only with the regular use of biologically
active additives. Plant-based bioflavonoids are popular
food additives, e.g. rutin, quercetin, dihydroquercetin,
eriodiktiol, resveratrol, etc. [4]. There are complex
compounds that protect DNA from damage in the
presence of hydrogen peroxide [5].
The growing prevalence of multiresistant bacterial
pathogens has become a worldwide problem in the
early XXI century. Infectious diseases remain a
serious problem worldwide. When bacteria, fungi, and
parasites become resistant to antimicrobials, it reduces
the efficacy of drugs and preventive treatment. More
and more microorganisms can withstand vaccines
and antibiotics. For instance, methicillin-resistant
Staphylococcus aureus is resistant to vancomycin [6].
The World Health Organization has already emphasized
the need to develop new antimicrobial molecules
because conventional antibiotics are growing helpless,
especially in fighting the so-called ESKAPE pathogens
with their gradually increasing antibiotic resistance:
Enterococcus faecium, Staphylococcus aureus,
Klebsiella pneumoniae, Acinetobacter baumanii,
Pseudomonas aeruginosa, and Enterobacter [7].
Fungal infections also cause high morbidity and
mortality, especially in immunocompromised HIV
and cancer patients. The growing cancer incidence is
another global health concern as it remains one of the
most common causes of death worldwide. The recent
advances in cancer treatment, e.g. chemotherapeutic
drugs, have significantly improved the prognosis and
survival of cancer patients [7].
Antimicrobial nanoparticles and nanocomposite
materials. Nanoparticles can target bacteria as an
alternative to antibiotics. Nanotechnology can be
especially useful in the treatment of bacterial infections.
Nanoparticles cover antibacterial coatings of implantable
devices to prevent infection and promote wound
healing. They are used in treating diseases as antibiotic
delivery systems. In bacteria detection systems, they
facilitate microbial diagnostics. They also can control
bacterial infections in antibacterial vaccines [8]. Metal
nanoparticles have a pronounced wound healing effect.
Nanocomposite materials of silver, gold, platinum,
and iron possess high antimicrobial activity when
stabilized by arabinogalactan, which is a natural
polysaccharide, as well as by other metal nanoclusters.
A biologically active complex called Fullerene
C60/Tween 80 affects the main pathogenesis of wound
process [9]. There have been studies of the sorption
activity of Acetobacter xylinum cellulose nano-gel films
in various biological media in comparison with other
sorbents.
Antibacterial bimetallic surfaces of implant
biomaterials have also become focus of scientific
attention [10]. The research featured platinum and silver
nanoparticles that were 1.3–3.9 nm thick and 3–60 nm
wide. To create an antimicrobial surface, they were
subjected to magnetron sputtering on a titanium substrate,
both separately and together. Sequential sputtering
of silver and platinum nanoparticles increased the
antimicrobial activity, if compared to co-sprayed silver
and platinum samples or pure silver patches (Fig. 2).
Researchers have synthesized gold and platinum
nanoparticles coated with a pyrimidine-based
ligand [11]. The nanoparticles interacted with DNA
due to hydrophobic forces and demoinstrated a good
antioxidant activity. In addition, they possessed
antimicrobial properties against Escherichia coli,
Klebsiella pneumonia, Pseudomonas fluorescens,
Shigella sonnei, Staphylococcus aureus, Aspergillus
niger, Candida albicans, Candida tropicalis, and
Rucoropus mucis indica.
Antimicrobial nanoagents can be used in dentistry,
medical devices, and food industry [12].
Antimicrobial nanoparticles and peptides can
become new non-antibiotic antimicrobials that kill
bacteria in biofilms. Biofilms can be produced by several
species or one strain of bacteria. A biofilm is a template
Figure 2 Antibacterial activity of silver and platinum
particles [10] coating of one or more strains of bacteria that adhere to
biological or non-biological surfaces. Biofilms increase
the resistance of microorganisms to antimicrobial agents
by producing extracellular polymeric substances.
Many bacterial pathogens have developed antibiotic
resistance, resulting in infections that cannot be treated
with conventional antibiotics. New non-antibiotic
antimicrobial agents, e.g. silver nanoparticles or new
antimicrobial proteins, can bind and oxidize thiol
groups, block DNA replication, alter the expression of
bacterial genes and denaturing enzymes, induce reactive
oxygen species, or damage bacterial membranes.
Antimicrobial proteins, e.g. antimicrobial peptides, and
natural enzymes, e.g. those derived from insects and
bacteria, also demonstrate antibacterial properties [2, 3].
As a result, they can be used in biomedicine and food
industry as antibacterial agents. The antimicrobial
properties of peptides are not as strong as those of
conventional antibiotics, but sufficient enough to kill
pathogenic microorganisms. The mechanisms of their
action remain unclear, but they are believed to target
bacterial membranes and intracellular molecules.
Chronic infections lead to inflammation and deplete
immune defense, thus contributing to the proliferation
of cancer cells. Cisplatin (CDDP) has been approved
by the Food and Drug Administration (FDA) as an
antitumor drug, which is now widely used to treat
various types of cancer. Cisplatin owes its antitumor
properties to the fact that it affects DNA directly [13].
DNA alkylation suppresses the biosynthesis of
nucleic acids and kills the cell. However, cisplatin
has no targeted effect: it spreads in all biological
fluids and body tissues, causing renal function
impairment, anaphylactic reactions, leukopenia,
thrombocytopenia, anemia, and neuropathy [14].
The antiproliferative effect that cicplatin produces on
rapidly dividing cells explains its toxic impact on the
functional state of organs and tissues.
As a result, scientists around the world have been
trying to develop more effective antitumor platinumbased
drugs with fewer complications. Currently, it is
one of the most urgent tasks of bioorganic chemistry
and biotechnology. The introduction into the internal
sphere of a complex of powerful antiproliferative and
functionally active ligands is another strategic direction
in the search for methods of highly effective agents.
Structural analogues of clinically tested platinum
complexes have been subjects of numerous studies in the
recent decades. Most of them feature monofunctional
platinum (II) complexes that carry only one labile
ligand, each complex binding to DNA only once [15].
The nature of the ligand and its coordination type
affect the reactivity of the central atom. Coordination
changes not only the thermodynamic stability and
kinetic lability of the complex, but also its lipophilic
properties. It either stabilizes or destabilizes the
oxidative state of the central atom.
Biopolymers: polysaccharides and peptides.
Micellar systems. Metals can produce complex
biologically-active biopolymers with antimicrobial and
antitumor properties.
Galactan-containing polysaccharides are known for
their high biological activity and immunomodulatory
effect. Arabinogalactans contain numerous galactose
and arabinose residues, which allow them to interact
with asialoglycoprotein receptors. This valuable property
makes it possible to use these polysaccharides to deliver
substances that are unable to pass through the outer
membrane into the cell. For instance, Starkov et al. used
arabinogalactan to deliver platinum into tumor cells [16].
Platinum has an antitumor effect as part of cisplatin,
which is widely used in cancer treatment [14]. Starkov
et al. also proved the antitumor effect of the equimolar
platinum-arabinogalactan complex based on the
interaction of cis-diamine(cyclobutane-1,1-dicarboxylate-
O,O’)platinum (II) with a polysaccharide [17].
Popova and Trifonov analyzed research results
published over the past 15 years which featured the
synthesis and biological properties of analogues
and derivatives of amino acids with tetrazolyl
fragments [18]. They concluded that tetrazolyl analogues
and derivatives of amino acids and peptides have a
great potential for medical chemistry. Tetrazoles are
polyazitous heterocyclic systems which include four
endocyclic nitrogen atoms. They are able to exhibit the
properties of acids and bases, as well as form strong
hydrogen bonds with proton donors and, less often, with
proton acceptors. They are metabolically stable and can
penetrate biological membranes. Another promising area
is the synthesis of linear and cyclic peptides based on
modified amino acids with a tetrazolyl fragment. Finally,
some tetrazole-containing amino acids and peptides
possess a high biological activity and can become a
source of new drugs [18].
Porphyrins are tetrapyrrole compounds that
form metal porphyrins when interacting with metal
compounds, and metal porphyrins can easily enter into
electrophilic substitution reactions. In addition, free and
metal-bound porphyrins are easily reduced to produce
mono- and dianionic compounds. Their nucleophilic
properties allow them to interact with proton donors.
Simulated solutions of porphyrin compounds help study
photo-oxygenation.
Platinum-bound porphyrins can inhibit multiresistant
bacteria, e.g. Staphylococcus aureus [19].
Tetra-platinum (II) porphyrin increased its hemolytic
activity when exposed to light. Lopes et al. proved
that platinized porphyrins had a good potential
for wastewater treatment, biofilm control, and
bioremediation since they can be used for microbial
photodynamic inactivation [19].
Proline derivatives are known to possess
antibacterial activity. Thioproline is an antioxidant,
while phenylproline derivatives inhibit the Staphylo302
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coccus aureus sortase SrtA isoform [20]. Gram-positive
bacteria produce surface proteins that promote the
attachment of the bacterial cell to the host and prevent
phagocytosis. During catalysis, sortase enzyme sorts
surface proteins on the bacterial cell wall. Surface
proteins then bind covalently to the bacterial cell wall
through the catalyzed S. aureus SrtA transpeptidase
reaction. Deactivation of SrtA genes of gram-positive
microorganisms inhibits the fixation of surface proteins
and reduces the virulence of the bacterium. Antibiotics
are not the only S. aureus SrtA inhibitors: peptides,
plant extracts, and low-molecular-weight organic
compounds have the same properties [20].
Therefore, biopolymers and micellar systems with
their ability to penetrate biological membranes can
deliver metal complexes into cells.
Complex platinum and palladium compounds.
Drugs based on organic ligand complexes exhibit
a greater antimicrobial effect compared to organic
pharmaceuticals. Complexation produces a synergistic
effect between the organic ligand and the complexing
agent. Chelates of platinum, iron, iridium, rhodium,
ruthenium, palladium, cobalt, and nickel have a
reputation of effective therapeutic agents.
Metal-containing active centers with a stable,
inert, and non-toxic nature are quite rare in biological
systems. They owe their activity to the bioavailability
of the complexes. Metal complex-based drugs facilitate
the transport of organic ligands towards the bacterial
cell. Palladium complexes proved highly effective
against resistant forms of microorganisms. For instance,
tetracycline palladium (II) complex appeared sixteen
times more effective against tetracycline-resistant
bacterial strains of E. Coli HB101/pBR322 than
traditional drugs [6].
There are a huge number of pharmacologically active
heterocyclic compounds. Advanced medical chemistry
has made it its main task to study the antimicrobial
and antitumor properties of platinum and palladium
complexes with heterocyclic ligands.
Benzothiazole derivatives are one of the most
popular pharmacologically known heterocyclic
compounds. Benzothiazole and its analogues
demonstrate a wide range of biological properties, e.g.
antitumor, antimicrobial, anticonvulsant, antiviral,
antituberculous, antimalarial, anthelmintic, analgesic,
anti-inflammatory, antidiabetic, fungicidal, etc. [21].
Thiazole nuclei that can be coordinated to metal atoms
are often used as an ambidentate ligand in biologically
active complexes.
Thiosemicarbazone and its derivatives can be used
as synthetic antiviral agents. They are heterocyclic
ligands and contain nitrogen, sulfur, and oxygen donor
atoms. Platinum (II) and palladium (II) complexes with
thiosemicarbazones exhibit anti-tuberculosis activity
against Mycobacterium tuberculosis [22].
Suleman et al. described Schiff-base complexes that
contained donor atoms of nitrogen, sulfur, and oxygen
and possessed antimicrobial and antitumor activity. The
antibacterial activity of these multi-dentate ligands and
their complexes demonstrated great prospects pharmacy
and agricultural chemistry. Coordination compounds
of transition metals owe their unique configuration and
chemical lability to their specific electronic and steric
properties, which make them sensitive to the molecular
environment [23].
The antimicrobial and antitumor properties of these
complexes depended on the electron-donor and acceptor
substituents in the aromatic ring. Bioligands modified by
hydrophilic groups appeared to increase the solubility of
compounds [24].
Platinum (II) complexes obtained from
functionalized aroylaminocarbo-N-thioyl prolineates
also demonstrated antibacterial and antifungal
properties [25]. Sulfur and oxygen atoms allowed
aroylaminocarbo-N-thioyl ligands to coordinate
bidentally. Non-electrolyte complexes had a squareplanar
configuration.
Mawnai et al. synthesized complexes with
N-coordinated pyridylpyrazolyl ligands that formed
a six-membered metallocycle [26]. They conducted
in vitro studies of the antibacterial activity of ligands
and their complexes. The research featured both
gram-negative (Escherichia coli and Pseudomonas
aeruginosa) and gram-positive (Staphylococcus aureus
and Bacillus thuriengiensis) bacteria. The cationic
nature of the complexes made them more effective
against the gram-negative bacteria.
Bakr et al. synthesized organometallic platinum
and palladium complexes with heterocyclic derivatives
of pyrazolone [5]. Pyrazolone derivatives had a fivemembered
ring with an additional keto group, which
allowed them to form chelates. They studied the
biological activity of azo-compounds to use them as
antitumor, antioxidant, and antimicrobial agents. They
also assessed their nuclease activity against DNA.
They performed an MTT lab-test on four human
cancer cell lines to study the antitumor activity of
the compounds in question. The cell lines included
hepatocellular carcinoma (HePG-2), colorectal cancer
(HCT-116), human prostate carcinoma (PC-3), and breast
carcinomas (CMC-7) [5].
As a rule, researchers employed standard methods to
study the antimicrobial activity of the abovementioned
compounds, e.g. the cut-plug method. Some experiments
featured strains of pathogenic bacteria, e.g. Escherichia
coli, Staphylococcus aureus, Bacillus subtilus,
Salmonella typhi, and Proteus spp, or such malicious
fungi as Candida albicans and Aspergillus niger [5]. An
in vitro anntioxidant analysis of pyrazolone derivatives
and their metal complexes made it possible to compare
the results of erythrocyte hemolysis. The palladium
complexes demonstrated a greater antioxidant activity
in comparison with platinum complexes. The free
ligand had a more prominent increase in the antioxidant
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activity, compared to metal complexes. This result could
be explained by a greater ability to charge transfer of the
condensed ring system. It increased the ability of the
heterocycle to stabilize unpaired electrons of the azocompound,
thus binding free radicals.
Chitosan is an antimicrobial agent that can destroy
bacteria, filamentous fungi, and yeast. Chitosan is
a copolymer of 2-amino-2-deoxy-D-glucopyranose
and 2-acetamido-2-deoxy-D-glucopyranose combined
with β (1 → 4), which gives it high biocompatibility
and biodegradability. Chitosan is widely used in food
industry, agriculture, and medicine.
The antimicrobial activity of chitosan and its
derivatives depend on pH, type of microorganisms,
molecular weight of the biopolymer, and the degree
of its deacetylation. If a chemical change occurs in
the structure of the amino- and hydroxyl groups of
the glucosamine chains of the biopolymer, it can
affect not only the solubility and stability of chitosan,
but also its antimicrobial activity. Berezin et al.
described the synthesis of water-soluble conjugates
of chitosan with tetrazoles. They bound tetrazoles by
the chlorohydroxypropyl groups of N-(3-chloro-2-
hydroxypropyl) chitosan, while the other part of the
groups interacted with the amino groups of the polymer,
which led to intra- or intermolecular crosslinking [27].
The antimicrobial properties increased as a result of the
complexation of chitosan with various metals.
Barbosa et al. developed new platinum (II) and
palladium (II) complexes with biopolymer amphiphilic
Schiff-bases to increase the biological activity of
chitosans. They performed the binding by fixing
chitosans in templates of various molecular weights.
The chitosans were modified with salicylic aldehyde
and glycidol [24]. They introduced salicylaldehyde to
obtain the complexing Schiff-base sites in the chitosan
template. Glycidol made it possible to increase the
water solubility of the resulting biopolymer complexes.
The new complexes underwent spectral and thermal
testing for antimicrobial and antitumor activity.
When compared to the free ligand, the complexes
demonstrated a higher antibacterial efficacy against
gram-negative bacteria Pseudomonas syringae than
against Fusarium graminearum fungi. They also
demonstrated a high antitumor effect on MCF-7 breast
cancer cells, with certain selectivity for non-tumor cells
(Balb/c 3t3 clone A31) depending on the concentration
and molar mass. In higher concentration, all complexes
synthesized with different molecular weights of the
polymer template decreased the viability of MCF-7
cancer cells [24].
Bobinihi et al. synthesized dithiocarbamide
ligands based on primary amines, N-phenylaniline,
4-methylaniline, and 4-ethylaniline [28]. S,S-binding
resulted in bidentate coordination, which led to the
formation of squared complexes of platinum (II)
[Pt (L) 2] and palladium (II) [Pd (L) 2]. They exhibited
antimicrobial activity against gram-negative bacteria
(Escherichia coli, Klebsiella pneumonia, and Pseudomonas
aeruginosa), gram-positive bacteria (Bacillus
cereus and Staphylococcus aureus), and fungi (Candida
albicans and Aspergillus flavus).
The mechanisms of the antitumor effect changed
when naphthalenbenzimidisole was introduced
as a ligand into the platinum-metal system. The
antiproliferative activity, drug resistance, and toxicity
increased. Liang et al. invented a synthesis method for
naphthalene benzimidisole-platinum (II) complexes [29].
They studied their antiproliferative activity for eight
cancer cell lines, namely Hela, HepG2, SKOV3,
NCI–H460, BEL–7404, SMMC–7721, U251, and A549.
Unlike cisplatin, the naphthalenbenzimidisole complexes
did not show resistance to A549-CDDP. The mechanism
of the antitumor effect appeared due to the covalent
binding to DNA and an increase in the expression level
of intracellular type I. An in vitro experiment showed
that several complexes proved sensitive and selective
to cell lines SMMC-7721 and U251 and possessed low
toxicity to normal HL-7702 cells.
Antimicrobial activity depends on the alkyl chain
length of N-substituted imidazolium salts, where
long alkyl chain compound with 8–16 carbon atoms
reached the lowest values of the minimum inhibitory
concentration. While alkyl chains under six carbon
atoms are usually inactive, the alkyl chain length affects
the functioning of the bacterial membrane [30, 31].
When a long hydrocarbon chain integrates with a
lipid bilayer of the cell membrane, cell contents may
start leaking out [32]. The antimicrobial activity
of imidazolium salts depends on such factors as
hydrophobicity, adsorption, critical micelle concentration,
and the transport rate in aqueous media.
Meng et al. synthesized a number of platinum (II)
complexes with substituted 3-(2’-benzimidazolyl)
coumarins (1-benzopyran-2-one) [33]. The complexes
exhibited a high cytotoxic activity in vitro against
cisplatin-resistant cancer cells, namely SK-OV-3/DDP
with a low IC50.
Choo et al. described a wide range of organometallic
drugs with N-heterocyclic carbene (NHCs) ligands [34].
The new complexes were insoluble in most solvents
except dimethyl sulfoxide. Complexes with several
conjugated rings are highly hydrophobic and do not
affect the activity of gram-negative bacteria. Inhibition
of the growth of gram-positive bacterial strains occurs
at low micromolar concentrations of the synthesized
complexes. The different susceptibility of grampositive
and gram-negative bacteria results from their
morphological differences, namely the permeability
of the outer layer of bacteria. The difference in
susceptibility can be explained by their morphological
differences between gram-positive and gramnegative
bacteria. Gram-positive bacteria have a lower
permeability of the outer peptidoglycan layer, while

the outer membrane of gram-negative bacteria contains
structural lipopolysaccharide components. They make
the cell wall impervious to lipophilic solutions. As a
result, porins, membrane transport proteins, form a
selective barrier for hydrophilic solutions [34]. The
part of the channel protein that is responsible for
transmembrane transport opens and closes depending on
the hydrophilicity of the complex.
The synthesis of platinum (IV) antitumor drug
precursors relies on the fact that the oxidation state
of platinum (IV) leads to a greater stability than their
platinum (II) analogues. The stability of platinum (IV)
precursors results from their resistance to reduction,
inertness to ligand exchange, and reactivity [35].
There have been successful attempts to synthesize
antimicrobial platinum complexes with coumarin
derivatives as heterocyclic biologically active
ligands [36]. They inhibited the cyclooxygenase enzyme
by coumarin complexes of platinum (IV) with cisplatin
and oxaliplatin centers.
Oxygen atoms allow carboxylate ligands of RCO2
–
to possess electrodonor properties. Their coordination
is monodentate, bidentate, and even tetradentate.
The carboxylate platinum and palladium complexes
are analogues of biologically active compounds. The
acidoligand and synthesis conditions proved to affect
the formation of the internal coordination sphere.
The system of hydrogen bonds and/or π – π-stacking
interactions between aromatic ligand segments also
produced a certain effect on the processes of selforganization
of complexes into supramolecular
structures [37].
Carboxylate metal complexes often take the form of
polynuclear compounds due to the oligomerization of
oxo- and hydroxo-functional groups, thus developing
М-О-M structural units. There are platinum (IV)
carboxylate complexes with anticancer activity [35, 38].
Al-Khathami et al. synthesized several Schiff bases
with various primary aromatic amines derived from
pyridine-2-carboxaldehyde as ligands for platinum
(II) complexes [39]. They studied their antimicrobial
activity in vitro using the cut-plug method in nutrient
media. Microorganisms were plated in wells filled
with the test solution of ligands and complexes with
subsequent incubation. Some complexes and ligands
proved to have inhibitory effect on such pathogenic
human bacteria as Escherichia coli, Bacillus subtilus,
Salmonella typhimurium, Klebsiella pneumoniae,
Staphlococcus aureus, Pseudomonas aeruginosa, and
Candida fungus. Studies of DNA binding showed that
the electron-withdrawing groups facilitated the binding
of platinum (II) complexes containing the Schiff
base pyridyl ligands (Fig. 3). The complexes with an
electron-withdrawing group demonstrated the highest
antimicrobial effect. The complex with a nitro group
proved effective against bacteria, but not against fungi.
The acetyl group increased antimicrobial activity against
almost all strains. Due to the hydroxyl group, free
ligands possessed a higher antimicrobial activity against
gram-negative bacteria, compared to their platinum (II)
complexes.
Platinum complex compounds are not the only
platinum group metals with pronounced antimicrobial
and antitumor properties. Gold, silver, iridium, rhodium,
and ruthenium complexes demonstrate similar activities.
The cytotoxicity of gold complexes usually consists in
the inhibition of thiol-containing enzymes. When gold
binds with thiol groups, the reductases and proteases of
cancer cells become potential targets for gold complexes
(Fig. 4). Inhibition of the activity of these enzymes
can disrupt the redox state of the cell and increase the
production of reactive oxygen species (ROS), thus
causing cellular oxidative stress and leading to its
own apoptosis. This mechanism differs from that of
platinum-based drugs [40].
Polynuclear platinum and palladium complexes.
Binuclear and polynuclear platinum complexes have
recently proved biologically active and antimicrobial.
Bridging ligands contribute to the formation of
cyclometallic complexes. Polynuclear compounds
exhibit properties different from those of free ligands
and monomeric complexes.
Johnstone et al. studied non-classical platinum (II)
complexes with trans-geometry or a monofunctional
Figure 3 Methods of binding a mononuclear complex with
a protein [39]
Figure 4 Binding of silver with thiol groups [40]
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Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311
coordination center, as well as polynuclear platinum (II)
compounds, platinum (IV) prodrugs, photoactivated
platinum (IV) complexes, and other precursors [41].
Ligands and complexes differ in chemical
nature, size, and geometric shape, which affect their
DNA-binding properties. A detailed study of the method
of binding polynuclear complexes of platinum with
DNA produced a mixed result. The complexes were able
to interact directly with DNA due to covalent binding,
electrostatic forces, or intercalation [42]. Groove binding
proved to be the cause of cell apoptosis [43].
Complexes owe their activity to the formation of new
adducts with DNA. As a result, there are three important
aspects to their binding: DNA pre-association, formation
of DNA adducts, and induced conformational changes
in DNA [44]. Multinuclear platinum complexes contain
two or more bound platinum centers that can covalently
bind to DNA and, therefore, are capable of forming a
completely different kind of DNA adducts compared
to cisplatin and its analogues. Multicore complexes
represent a completely new paradigm of biologically
active complexes, in particular, for platinum-based
anticancer agents.
In our previous research, we proved that the bonds of
bridged halide ligands had a greater lability, compared
with the terminal ones [45]. This fact made it possible
to introduce polynuclear platinum complex compounds
into the biosystem. Their aquatization resulted in
a break of bridging bonds with the formation of
monomeric complexes.
P,N- and S,N-bidentate ligands have the properties
of both soft and hard bases. As a result, they can
direct organization of the metal coordination sphere
(Fig. 5), as well as form bimetallic and polynuclear
systems [43].
In our previous studies, we also described a
method for the synthesis of binuclear complexes of
divalent platinum. According to this method, amino
acids (glycine, alanine, and valine) bound with two
central atoms simultaneously via two donor atoms, i.e.
bridges [(NH3)2Pt(μ-N,O-L)2Pt(NH3)2](NO3)2 [46]. The
coordination of amino acids led to the formation of
chelates, while the presence of a biogenic ligand in the
internal coordination sphere reduced the overall toxicity
of the platinum complex. The compounds showed
cytotoxic activityI.
Popova and Trifonov synthesized antimicrobial
binuclear platinum (ΙΙ) complexes with tetrazole
and 5-methyltetrazole with the composition of cis-
[{Pt(NH3)2(L-H)Cl}2]Cl [18].
Lunagariya et al. studied the antibacterial activity
of platinum (II) binuclear complexes based on pyrazolo
[1,5-a] pyrimidine with neutral tetradentate ligands.
The general formula was [Pt2LCl4] [42]. The research
featured five test organisms: two gram-positive
(Bacillus subtilis and Staphylococcus aureus) and
three gram-negative (Escherichia coli, Pseudomonas
aeruginosa, and Serratia marcescens). It also included
an in vitro study of anti-tuberculosis activity against
Mycobacterium tuberculosis H37Rv strain.
Antibacterial actions include several phases of
inhibition: cell wall synthesis, cell membrane functions,
protein synthesis, nucleic acid synthesis, and folic
acid synthesis. Chelation makes it possible to increase
the values of the minimum inhibitory concentration
of the complexes. This effect can be explained by the
Tweedy’s chelation theory: chelation allows the complex
to penetrate the cell membrane. The complexes are
toxic partially because the metal-ligand bond is strong.
The toxicity differs from the type of substituent present
in the synthesized compounds (Fig. 6) [42]. Active
substituents in ligands have a high lipophilicity, which
allows them to penetrate the complexes through the cell
membrane. Complexes with a high-electronic substituent
NO2
– in its phenyl ring exhibit a greater antibacterial
and anti-tuberculosis activity. Nitro groups act as
chemical isosteres for oxygen atoms in the heterocyclic
base of thymidine. However, they also participate in
the “strong” O – H bond. As a result, the bond exhibits
greater DNA-binding and antimicrobial activity than
other complexes. The phenyl group is replaced with
donor substituents, e.g. methoxy- or methyl group, and
a hydrogen atom in the para position. Subsequently,
the antibacterial activity against P. Aeruginosa and
E. coli decreases, while acceptor chloro-, nitro-, and
fluorosubstituents increase their efficacy against
S. Marcescens and B. Subtilis [42].
Rubino et al. synthesized binuclear platinum (II)
complexes with fluorinated heterocyclic ligands:
5-perfluoroalkyl-1,2,4-oxadiazolylpyridine and 3-perfluoroalkyl-
1-methyl-1,2,4-triazolylpyridine [47]. Chlorine
atoms served as bridges between the two platinum
atoms. The complexes showed antimicrobial activity
against Escherichia coli, Kocuria rhizophila, and two
strains of Staphylococcus aureus. Azolate-bridged
polynuclear platinum complexes formed DNA adducts
as a result of additional electrostatic interaction.
I Salishcheva OV, Moldagulova NE, Proskynov IV. Investigation
of the biological activity of organometallic complexes of platinum.
XXI Mendeleev Congress on General and Applied Chemistry; 2019;
St. Petersburg. St Figure 5 Binding of DNA with binuclear complex [43] . Petersburg, 2019. p. 334.
306
Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311
Icsel et al. obtained mono- and binuclear
palladium (II) and platinum (II) complexes with
ligands L1 = 5,5-diethylbarbiturate and pyridine
derivatives L2 = 2-phenylpyridine, 2,2’-bipyridine and
2,2’-dipyridylamine. The general formula was [M(L1-N)2
(L2-N,N′)] and [M2(μ‑L1-N,O)2(L2-N,C)2] [48]. The
complexes appeared to have similar DNA binding
mechanisms.
There have been much fewer medical studies
concerning palladium (II) complexes for medicinal
use. Palladium (II) and platinum (II) complexes have
different chemical properties because palladium
compounds have a greater lability of the ligandcomplexing
bonds. As a result, hydrolysis processes get
accelerated, and the amount of dissociation products
increases, e.g. aqua- or hydroxo-complexes, which are
unable to fulfill their biological functions. To eliminate
this factor, large heterocyclic and chelate ligands have to
be introduced into the internal sphere.
Rubino et al. synthesized antibacterial palladium
complexes with aromatic nitrogen, sulfur, and oxygencontaining
ligands. They described the synthesis of
binuclear platinum (II) and palladium (II) complexes
with the 2,2’-dithiobis-benzothiazole (DTBTA) ligand
[Pd2(μ-Cl)2(DTBTA)2]Cl2. The research included an
in vitro analysis of their antitumor activity against
human breast cancer (MCF-7) and hepatocellular
carcinoma (HepG2), as well as against Escherichia coli
and Kokuria rhizophila. The complexes proved to have
a greater antimicrobial effect against gram-positive
bacteria than cisplatin. The low activity against gramnegative
bacteria was explained by the fact that these
bacteria have an additional outer membrane, which can
interfere with the absorption of both compounds.
Terbouche et al. studied palladium (II) and
ruthenium (III) binuclear complexes with phenylthiourea
derivatives, namely their antibacterial properties,
antioxidant activities, and stability (Fig. 7) [49]. They
used the spectrophotometry method to assess the
formation constants of the new Schiff-base alkali metal
complexes and the systems formed by these chelates and
cholesterol.
Chakraborty et al. described the synthesis and
characteristics of binuclear palladium (II) complex
[(3,5- dimethylpyrazole)2Pd2(μ-3,5-dimethylpyrazolate)2
(2,6-dipicolinate)] [50]. It was a dimer connected by
two 3,5-dmpz units. One palladium atom contained
two protonated 3,5-Hdmpz ligands and the other – one
bidentate 2,6-dipicolinate, which made the complex
asymmetric. The central nucleus of Pd2N4 consisted of
six elements. It was a boat-like structure with palladium
atoms located at the tops. The molecules assembled in
an elongated zigzag one-dimensional network formed
by 3,5-Hdmpz-carboxylate (2,6-dipic 2-) hydrogen
bonds. The complex demonstrated antimicrobial
activity against Bacillus subtilis, Escherichia coli,
and Aspergillus niger. The minimum inhibitory
concentration was 100 μg/mL.
Another study featured pyrazolate binuclear
Palladium (II) complex [Pd2(μ-dppz)2(Hida)2]·CH3
ОН·2Н2O (dppz = 3,5-diphenylpyrazolate) with
monoprotonated iminodiacetate (Hida). It demonstrated
antimicrobial activity against Bacillus subtilis [51]. The
donor atoms of oxygen and nitrogen coordinated the
pyrazolate ligand.
A binuclear pyrazolate square-planar palladium
complex Pd2Cl4L2 (L = 5-methyl-5-(3-pyridyl)-2,4-
imidazolidenedione ligand) with cis- and transconfigurations
also showed antimicrobial activity [52].
The trans-isomer appeared more stable in the liquid
and gaseous phase than the cis-isomer. The pyridinetype
nitrogen atoms provided for the square-planar
geometry around the metal center. Each palladium
atom was coordinated by one nitrogen atom and three
chlorine atoms, one serving as terminal and two as
bridging ligands (Fig. 8). The initial mononuclear
complex and the binuclear palladium complex were
tested for antibacterial activity against six types of
microorganisms: Staphylococcus aureus (ATCC 6633),
Staphylococcus saprophyticus (ATCC 15305), Escherichia
coli (Lio), Proteus vulgaris (Lio), Serratia
marcescens (PTCC 1330), and Bacillus cereus (ATCC
7064). Bacterial growth was studied by disk diffusion,
while the minimum inhibitory concentration of the
Figure 6 Coordination of tetradentate pyrazolo-pyrimidine
in the binuclear platinum (II) complex [42]
Figure 7 Tridentally coordinated bis-[1-(2-[(2-hydroxynaphthalen-
1-yl)methylidene]amino}ethyl)-1-ethyl-3-phenylthiourea]
ligand in a binuclear palladium (II) complex [49]
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Salishcheva O.V. et al. Foods and Raw Materials, 2020, vol. 8, no. 2, pp. 298–311
chemicals was determined by in vitro dilution. The
microorganisms were cultured in harvest broth and
nutrient agar (Oxoid Ltd.). The agar culture medium
included 0.5% of peptone, 0.3% of beef or yeast
extract, 1.5% of agar, 0.5% of NaCl, and distilled water;
pH = 6.8 at 25°С [52].
The compounds inhibited the metabolic growth of
bacteria to varying degrees. The binuclear complex had
a higher activity compared to the free ligand, while
the ligand activity became more pronounced when
coordinated with the metal. The increased activity of
metal chelates could be explained by Tweedy’s chelate
theory: the polarities of the ligand and the complexing
agent are restored by balancing the charges throughout
the whole chelate ring. As a result, the lipophilic
nature of the metal chelate increases and facilitates
its penetration through the lipid layer of the bacterial
membrane [53].
Plant extracts. Natural products or their extracts
possess antimicrobial properties, e.g. grape skin or
essential plant oils, e.g. of citrus fruits, wormwood,
mint, and ginger [54–57]. When used in combination
with nanoparticles, various functional essential oils
produce a synergistic effect against multidrug resistant
microbial pathogens (Fig. 9) [58].
CONCLUSION
Malicious microorganisms keep mutating. They
grow ever more resilient to drugs, which triggers a
never-ending search for new antimicrobial agents.
Drugs based on organic ligand complexes exhibit an
antimicrobial effect comparable to that of antibiotics.
The complexation leads to a synergistic effect between
the organic ligand and the complexing agent. Chelates
of platinum, palladium, silver, iron, iridium, rhodium,
ruthenium, cobalt, and nickel are therapeutic agents.
Complexes with enhanced bioavailability have a better
antimicrobial effect against pathogenic microorganisms.
Metal-based drugs facilitate the transport of organic
ligands towards the bacterial cell.
The reactivity of the central atom depends on the
nature of the ligand and the coordination method.
Coordination changes not only the thermodynamic
stability and kinetic lability of the complex, but also
the lipophilic properties that ensure the ability of the
complex to penetrate the cell membrane. It stabilizes
or destabilizes the oxidative state of the central atom.
When complexes with functional multi-dentate
ligands enter the internal sphere, it enhances the
antimicrobial effect. The presence of a biogenic ligand
in the coordination sphere reduces the general toxicity
of platinum and palladium complexes. Drugs based
on complexes with functional multi-dentate ligands
exhibit a greater antimicrobial effect compared to free
ligands. Inhibition of bacterial growth occurs at lower
concentrations of metal complexes.
Active metal centers with a stable, inert, and nontoxic
nature are of great value for biological systems.
Polynuclear and heteronuclear complexes increase
the number of active centers that block the action of
bacterial cells and improve the formation of cross-links
between different molecules. These valuable properties
Figure 8 Binuclear pyrazolate square-planar palladium
complex Pd2Cl4L2of (trans-configuration) with bridging
chloride ligands [52]
Figure 9 Antimicrobial effect of nanoparticles used with functional essential oils [58]

encourage researchers to synthesize new complexes
with antibacterial and antitumor properties. Due to
their ability for covalent binding to bacterial cell DNA,
polynuclear platinum and palladium complexes contain
two or more bound metal centers that can form a
completely different kind of DNA adducts, as compared
to mononuclear precursors.
The biological activity of structural analogues of
clinically approved platinum complexes has been focus
of scientific attention in the recent decades. A further
synthesis of complex antimicrobial compounds used
in combination with other agents may help to build up
a rich bank of substances with a great antimicrobial
potential. In the long term, further studies of their
antimicrobial action and the way it changes under
various factors will make it possible to promptly
overcome local or global outbreaks of infectious
diseases, such as the current pandemic.
CONTRIBUTION
Authors are equally related to the writing of the
manuscript and are equally responsible for plagiarism.
CONFLICT OF INTEREST
The authors declare that there is no conflict
of interest regarding the publication of this article.

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