Skip to main content
The Journal of Basic and Applied Zoology
Download PDF

A review on the anti-parasitic activity of ruthenium compounds

The Journal of Basic and Applied Zoology volume 85, Article number: 17 (2024) Cite this article

Abstract

Background

There are many infectious diseases in the world caused by parasites. Among them, toxoplasmosis, American trypanosomiasis, African trypanosomiasis, leishmaniasis, neosporosis and malaria are more common and contribute to a majority of the affected individuals.

Main body

Due to extensive use of antibiotics, antibiotic resistant strain of the parasites has developed. So, we need to develop a new metal ligand complexes which have many configurations, can overcome this drug resistance and also show significant results in elimination of the parasites. A series of anti-parasitic drugs have been formulated and tested for its activity. In this review, we have tried to see the interaction of different ruthenium drugs (arene ruthenium complex, ruthenium clotrimazole complex, etc.) on different parasites associated with the aforementioned diseases.

Conclusion

Combination of ruthenium to any organic ligand shows synergistic effects against parasite either by overcoming the drug resistance of the parasite or by binding with new targets due to the presence of ruthenium ion. The multiple modes of action generate an effective drug exhibiting anti-parasitic activity at low concentration.

Graphical abstract

Background

World is facing a major problem due to various parasitic diseases. A large sum of population dies due to such diseases but there is little economic investment for the search of new drugs to counter such diseases. It is more challenging to produce new drugs due to multi-drug resistance of the parasite (Li et al., 2015). Metallic compounds can be used for the treatment of diseases as they have structural diversity in their 3D configuration due to the presence of different geometry, metal ion, ligands, etc. (Morrison et al., 2020). The problem with organic compounds is their planar or linear structures which cannot be easily modified for recognition by a biomolecule. This is solved by the use of metal complex due to their complex 3D structure which results in strong interaction with the intercellular target (Morrison et al., 2020). Metal complexes have unique properties which are absent in organic compounds, like redox activation, production of reactive oxygen species (ROS) and targeting vital processes (Anthony et al., 2020; Claudel et al., 2020).

Synergism of a metal ion with a drug with anti-proliferative property leads to the formation of a complex with enhanced anti-proliferative property and decreases the cytotoxicity toward normal cells, thereby leading to inhibition of parasitic growth (Hess et al., 2015; Iniguez et al., 2013). For example, bismuth-based compounds are used for therapeutic purposes (Keogan et al., 2014). In this review, we are going to discuss the anti-parasitic potential of ruthenium compounds.

Methodology

The data presented in this review have been procured and summarized on the basis of the following principles.

Search strategy and inclusion criteria

This review consists of several literature survey of the anti-parasitic activity of ruthenium compounds against Toxoplasma gondii, Neospora caninum, Trypanosoma sp., Leishmania sp. and Plasmodium sp. Those compounds exhibiting optimum anti-parasitic effects have been enlisted and the corresponding mechanisms of action have been discussed briefly. The literature survey stressed on scientific research papers and review articles published from 1984 to 2022. The following keywords were included as part of the search strategy: ruthenium, Toxoplasma, Neospora, Trypanosoma, Leishmania, Plasmodium, anti-parasitic activity, malaria, toxicity, in vitro study, ER stress, clotrimazole, etc. Google Scholar and PubMed were the main databases used for searching relevant information.

Data extraction and analysis

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist was consulted because this review bears some characteristics of an overview, which in turn, is partially synonymous to a systematic review (Grant & Booth, 2009). The PRISMA flow diagram shows how the relevant data have been extracted and analyzed (Fig. 1) (Liberati et al., 2009).

Fig. 1
figure 1

PRISMA flow diagram

Full size image

Quality assessment

The quality of the studies included for quantitative analyses was assessed using the Critical Appraisals Skills Program (CASP) checklist with slight modifications (Table 1) (Critical Appraisal Skills Program (2018). CASP (Systematic Review) Checklist. [online] Available at: https://casp-uk.net/casp-tools-checklists/. Accessed: 20th July, 2023). A summary of the data obtained from such studies has been included in Table 2. During quality assessment of 18 short-listed literatures, it was observed that the contents of 9 articles had already been summarized in a previously published scientific review. Therefore, the single scientific review (Munteanu et al., 2021) was considered for quality assessment instead of the concerned 9 articles to avoid unnecessary complexity.

Table 1 Modified CASP Checklist
Full size table
Table 2 Summary of key findings in this review
Full size table

Main text

Chemical properties of ruthenium

Of the two redox potentials of ruthenium, Ru(III) is more inert than Ru(II) oxidation state. Ru(III) and Ru(II) usually form compounds with octahedral geometry that lead to interconversion of oxidation states without the requirement of large amount of energy for the associated structural rearrangement (Gasser et al., 2011; Zeng et al., 2017). Some enzymes like ascorbate reduce Ru(III) to its more reactive Ru(II) form. There are also some enzyme like cytochrome oxidase which can reverse the reaction and convert Ru(II) back to Ru(III) (Allardyce et al., 2005). The kinetic stability of the ruthenium drug depends on the ligand to which it binds. Different ruthenium drug complexes (Ru complexes) can be made which show high cytotoxicity against parasites (Munteanu et al., 2021). Ruthenium drugs have been mostly used to treat cancer. Simultaneously, they are found to be effective against helminth infections (Han Ang & Dyson, 2006; Hess et al., 2015; Küster et al., 2012).

Mechanism of action of ruthenium

Existing literature lacks a detailed understanding of the mechanism of action of ruthenium compounds, especially against parasitic diseases. However, the following discussion may provide insights into their possible routes of interaction and inspire further extensive research.

Ruthenium-DNA interaction

The diamine groups, the hydrophobic arene and the chloride leaving group of ruthenium arene complexes have important role in their mechanism of recognition of nucleic acids (Chen et al., 2003). Some ruthenium complexes intercalate with the DNA by non-covalent stacking interactions with DNA base pairs (Chen et al., 2003; Mishra & Mukherjee, 2006; Nyawade et al., 2014).

Inhibition of membrane sterol biosynthesis

Ruthenium clotrimazole complex shows anti-parasitic effects against Leishmania major. It easily passes the parasite’s membrane and upon hydrolysis liberates clotrimazole. This azole derivative then inhibits the cytochrome P-450 dependent C(14)-demethylation of lanosterol to ergosterol (Iniguez et al., 2016).

Effect on ultrastructure and membrane potential of mitochondria

Dinuclear thiolato bridged arene ruthenium complexes have been reported to cause alterations in the ultrastructure and membrane potential of mitochondria in bloodstream forms of Trypanosoma brucei. Such alterations include distortion of mitochondrial membrane with transformation of the mitochondrial matrix into an amorphous moiety having varying degrees of electron density or filling of the organellar interior with unknown filamentous structures, and the dose and time dependent effects of the complexes on the mitochondrial membrane potential (Jelk et al., 2019).

Modulation of endoplasmic reticulum (ER) stress pathway

Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339), a ruthenium compound metal complex, has been reported to generate reactive oxygen species (ROS) in colon cancer cell lines. ROS leads to activation of Nrf2 and the subsequent transcription of antioxidant response gene. ROS generation also leads to accumulation of misfolded proteins in the ER and subsequent ER stress. At low concentrations of NKP-1339 in HCT116 cells, GRP78, a key regulator of ER stress, is upregulated. GRP78 releases PERK, a transmembrane receptor of ER, which is then phosphorylated. Then, phosphorylation of eIF2α ensues, which leads to the inhibition of CAP-dependent translation. Consequently, the CAP-independent transcription factor ATF4 is upregulated. It translocates to the nucleus and induces expression of CHOP. CHOP downregulates Bcl-2 and activates death receptor 5 (DR5), thereby promoting apoptosis. (Fig. 2) (Flocke et al., 2016).

Fig. 2
figure 2

Modulation of pathway of ER stress mediated apoptosis by NKP-1339 in colon cancer cell. ATF4: Activating transcription factor 4; CHOP: C/EBP-homologous protein; DR5: Death receptor 5; eIF2α: Eukaryotic initiation factor 2 alpha; GRP78: Glucose regulated protein 78 kD

Full size image

Anti-parasitic activity against Toxoplasma gondii

Toxoplasma gondii belongs to the clades Alveolata and Diaphoretickes (Smith et al., 2021). It is life threatening to immune suppressed hosts like humans and other animals (Dubey, 2021). Its seroprevalence is found to be quite high in some African and European populations (Milne et al., 2020). Many such parasites follow auxotrophic pathway, and we can conjugate ruthenium with purines which can increase the uptake of drug by the parasite (Coppens, 2014). Such drugs can modulate the cell death machinery (Klinkert & Heussler, 2006).

A trithiolato bridged dinuclear Ru(II) arene conjugated with 9–(2–oxyethyl)–adenine unit inhibits proliferation of T. gondii tachyzoites at IC50 of 59 nM (Fig. 3A). When T. gondii is treated with this complex, the YOU2 family C2C2 zinc finger protein of the parasite binds to this compound (Anghel et al., 2021).

Fig. 3
figure 3

Ruthenium compounds exhibiting anti-parasitic activity against Toxoplasma gondii (A–C), Neosporacaninum (C–E) and Trypanosoma sp. (F–H). A–E arene ruthenium complexes; F, G ruthenium nitrosyls; H ruthenium-based clotrimazole drug. (The structures have been constructed using ChemDraw Pro 8.0)

Full size image

A dinuclear thiolato bridged arene ruthenium complex (Fig. 3B) exhibits an IC50 value of 1.2 nM against T. gondii. It affects the extracellular parasites and prevents them from adhesion, invasion and establishment in the host cell. It mainly binds to the T. gondii elongation factor 1α (TgEF1-α), affects the mitochondria and results in death of most of the tachyzoites within 48 h of treatment. It targets the cytochrome b/c1complex of mitochondria (Basto et al., 2017).

An η6-areneruthenium(II) phosphite complex (Fig. 3C) has been shown to exhibit an IC50 value of 18.7 nM against T. gondii parasite. 12 h after treating with the drug, lipid inclusions are found in the cytoplasm, the nuclear membrane appears fuzzy in appearance and chromatin threads are mostly located at the periphery of the nucleus of the tachyzoites when observed under TEM. After 36 h of treatment, the cytoplasm is completely disorganized and the organelles of the tachyzoites are hardly detectable (Barna et al., 2013).

Anti-parasitic effect on Neospora caninum

Neospora caninum is an apicomplexan parasite which exhibits the rapidly proliferating tachyzoite stage and the cyst forming bradyzoite stage which remains in the host for a longer period of time without showing any symptoms. They live in the immune compromised tissue, affect the immune system of the host and modulate it for their own benefit. The parasite causes neosporosis leading to abortion and maternal infertility in cattle and neurological disorder in dogs (Dubey & Lindsay, 1996; Innes et al., 2007; Lüder et al., 2009).

An η6-areneruthenium(II) phosphite complex (Fig. 3C) showed the IC50 value of 6.7 nM against N. caninum (Barna et al., 2013). The drug severely impaired the proliferation of the parasite.

Dinuclear trithialato bridged arene ruthenium complexes [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-p-CH3)3]Cl (Fig. 3D), [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-p-But)3]Cl (Fig. 3E) and [(η6-p-MeC6H4Pri)2Ru2(µ2-SCH2C6H4-p-But)2-(µ2-SC6H4-p-OH)]BF4 have shown an IC50 value of 15, 5& 1 nM against N. caninum, respectively. After the delivery of the drug, changes in the structure of parasite mitochondria was observed rapidly. After the delivery of the three drugs, within 6 h, large vacuoles appeared in the mitochondrial matrix. All the 3 compounds showed high lipophilicity and prompted toward their easy cellular uptake (Basto et al., 2019).

Anti-parasitic effect against Trypanosoma sp.

Trypanosoma sp. is a parasite of class kinetoplastida. This parasite is extracellular in nature and lives in the body fluids. They feed on blood and lymph of the host. Trypanosoma cruzi causes the Chagas disease (American trypanosomiasis) in humans. Trypanosoma brucei is a parasite which is mostly found in Africa (Cavalli & Bolognesi, 2009; Le Loup et al., 2011; Rivera et al., 2009). They show high proliferating power which resembles the proliferation of the cancer cells, and so, we can use anti-cancer drugs for treating such parasite infections (Gambino & Otero, 2012).

Trypanosoma cruzi

This disease affects more than 20 million people per year and result to death of approximately 50,000 people per year in South and Central America (Hotez et al., 2008; Kirchhoff, 2011; WHO Report, 2002). It affects humans in trypomastigote stage through its vector, the reduviid bugs, which suck blood from the host and help in transmitting the parasite by the deposition of the parasite loaded faeces on the host body surface. It can also be transmitted blood transfusion and organ transfusion (Bern et al., 2011; Schmunis, 2007).

trans-[Ru(NO)(NH3)4(isn)]3+ (Fig. 3F) and trans-[Ru(NO)(NH3)4(imN)]3+ (Fig. 3G) complexes forming trans-[Ru(NO)(NH3)4(isn)](BF4)3 (where isn stands for isonicotinamide) and trans-[Ru(NO)(NH3)4(imN)](BF4)3 (where imN stands for imidazole), are found to be effective against the parasite (Munteanu et al., 2021; Silva et al., 2007, 2009). Ruthenium nitrosyls on reduction result in release of trypanosomicidal NO.

cis-[Ru(NO)(bpy)2(imN)](PF6)3 and cis-[Ru(NO)(bpy)2SO3]PF6 show inhibitory effects on the T. cruzi glyceraldehyde 3-phosphate dehydrogenase through IC50 of 89 and 153 µM, respectively (Munteanu et al., 2021; Silva et al., 2010).

cis,trans-[RuCl(NO)(dppb)(5,5’-mebipy)](PF6)2 (where dppb stands for 1,4-bis(diphenylphosphino)butane and mebipy stands for 5,5’-dimethyl-2,2’-bipyridine) shows an IC50 value of 2.1 µM against the acute stage of the disease, i.e., trypomastigote and IC50 value of 1.3 µM against the chronic stage of the disease, i.e., amastigotes (Munteanu et al., 2021; Bastos et al., 2014).

Organoruthenium(II) compounds [Ru2(p-cymene)2(L)2]X2 (where L are bioactive 5-nitrofuryl-containing thiosemicarbazones and X = Cl or PF6 show anti-parasitic activity against both T. cruzi and T. brucei (Demoro et al., 2013).

Trypanosoma brucei

Trypanosoma brucei is a flagellated parasite and its subspecies T.b. rhodesiense and T.b. gambiense cause human African trypanosomiasis of which T.b. gambiense contributes to 80% cases of the disease (Giordani et al., 2016). They use tsetse fly as the vector. They live in the blood stream of the host (Priest & Hadjuk, 1994).

[(η6 -p-MeC6H4Pri)2Ru2(μ2-SC6H4-o-Pri)3]Cl is a dinuclear thiolato bridged arene ruthenium complex showing IC50 value of 4 nM against T. brucei (Jelk et al., 2019).

A ruthenium-based clotrimazole drug, [RuCp(PPh3)2(CTZ)](CF3SO3) (where Cp stands for cyclopentadienyl and CTZ stands for clotrimazole) (Fig. 3H) affects the trypomastigotes stage of the parasite with an IC50 value of 0.6 µM (Rodriguez Arce et al., 2015).

Anti-parasitic activity against Leishmania sp.

Leishmaniasis is a protozoan disease caused by a parasite belonging to the class kinetopastida and genus Leishmania. It is mostly present in the subtropical and tropical part of the world. It is transmitted by a sand fly which belongs to the phlebotominae subfamily. It causes three types of leshmaniasis which are cutaneous leishmaniasis which accounts for one third of the total affected individuals, visceral leishmaniasis which is also known as kala azar and mucocutaneous leishmaniasis. It affects around 2 million people every year (Den Boer et al., 2011). So, ruthenium complex drugs can be used for its treatment.

A ruthenium clotrimazole complex, [Ru(II)(η6 -p-cymene)Cl2(CTZ)], (Fig. 4A) shows an IC70 value of 29 nM against the amastigote stage of L. major (Martinez et al., 2012). It is also effective against epimastigotes of T. cruzi.

Fig. 4
figure 4

Ruthenium compounds exhibiting anti-parasitic activity against Leishmania sp. (A, B) and Plasmodium sp. (C). A–C ruthenium clotrimazole and chloroquine complexes. (The structures have been constructed using ChemDraw Pro 8.0)

Full size image

A ruthenium clotrimazole complex, [RuII(p-cymene)(bpy)(CTZ)][BF4]2 (Fig. 4B) shows IC50 of 15 nM against L. major (Martinez et al., 2012; Munteanu et al., 2021).

[RuCl2(Lap)(dppb)] shows anti-parasitic activity against L. amazonensis promastigote stage (Munteanu et al., 2021; Barbosa et al., 2014).

cis-[RuII(η2-O2CC10H13)(dppm)2]PF6 (bbato), cis-[RuII(η2-O2CC7H7S)(dppm)2]PF6 (mtbato), cis-[RuII(η2-O2CC7H7O2)(dppm)2]PF6 (hmxbato) (where dppm stands for bis(diphenylphosphino)methane) are effective against various leishmanial species (Costa et al., 2019).

Anti-parasitic activity of ruthenium compounds against Plasmodium sp.

Malaria is caused by a plasmodium parasite belonging to order haemosporida. Of the various species of plasmodium, Plasmodium falciparum is quite dangerous and accounts for 90% of global malarial mortality (Snow, 2015).

[RuCl2(CQ)]2 is an organometallic complex where CQ is chloroquine which itself has anti-malarial property (Fig. 4C). It is five times more active than CQ due to the more lipophilic character of the drug than free CQ (Munteanu et al., 2021). The drug binds to hematinand prevents haemozoin accumulation. In the aqueous solution, the drug is converted to [RuCl(OH2)3(CQ)]2[Cl]2 which is the active drug resulting in anti-malarial activity (Martinez et al., 2008; Munteanu et al., 2021).

[RuCQ(η6-C10H14)(N–H)]2+ is also an organoruthenium complex where η6-C10H14 stands for α-phellandrene group and N–H represents either 5,5’-dimethyl-2,2’-bipyridine, 2’-bipyridine, 4,7-diphenyl-1,10-phenanthroline or 1,10-phenanthroline group. This drug shows anti-malarial activity against the sexual stage and also against stages of the parasite which target the liver. It produces ROS leading to death of the parasite (Macedo et al., 2016; Munteanu et al., 2021).

Trinuclear Ru(II)-η6-p-cymene complexes where ruthenium centre is linked by pyridyl aromatic ether ligands have been found to show an IC50 of 240 nM against CQ sensitive and 670 nM against CQ resistant P. falciparum strains (Chellan et al., 2013; Munteanu et al., 2021).

Clinical trials

Various anti-tumour drugs have been used for the treatment of parasitic infections (Farrell et al., 1984; Gambino, 2011). Similarly, this review demonstrates the use of ruthenium complexes as anti-parasitic drugs. Till date, no ruthenium drug has been put up for clinical trial with respect to treatment of parasitic diseases. However, there are drugs like NAMI-A, NKP-1339, KP1019, which have reached the phase of human clinical trials for ruthenotherapy against cancer (Hartinger et al., 2008; Rademaker-Lakhai et al., 2004; Trondl et al., 2014). Extensive research is necessary for various ruthenium compounds to reach the stage of human clinical trials for the treatment of parasitic diseases.

Conclusion

From the data we have received, we are able to conclude that the combination of ruthenium to any organic ligand shows synergistic effects against parasite either by overcoming the drug resistance of the parasite or by binding to new targets due to the presence of ruthenium ion. The drug interaction with DNA produces ROS. The concerned drugs bind to different proteins and damage the process of cell membrane synthesis. This multiple mode of action adds up to generate an effective drug exhibiting anti-parasitic activity at low concentration. Ruthenium has two oxidation states, and it binds to different bioactive ligands. So, ruthenium drugs with selective activity can be developed using different ligands depending on the nature of the parasite. We should focus in developing new organometallic drugs that show considerable activity against parasites owing to their lipophilic character which results in their easy cellular uptake.

Limitation of current research

Existing literature on anti-parasitic activity of ruthenium compounds exhibit the limitations of poor solubility of the compounds in water, lack of proper understanding of their mechanisms of action and the lack of clinical research (Munteanu et al., 2021; Serrano-Ruiz et al., 2017).

Future perspectives

Ruthenium drugs have immense potential in exhibiting anti-viral, anti-bacterial, anti-cancer and anti-parasitic effects in vitro. However, in vivo studies are necessary to validate such claims. To achieve therapeutic victory, proper understanding of the mechanism of action and studies on the targeted delivery of such drugs is essential. In this review, we have investigated about anti-parasitic activity of different ruthenium conjugated drugs. Developing countries are facing loss of human resource due to parasitic diseases but still we keep a blind eye toward it. Focus on investment for the development of many ruthenium conjugated drugs and testing their toxicity toward the parasite can help in generating effective drugs against various parasitic diseases.

Availability of data and materials

Not Applicable.

Abbreviations

Acac:

Acetylacetone

ASK1:

Apoptosis signaling regulating kinase

Bpy:

2,2′-Bipyridine; Cp, cyclopentadienyl group

CQ:

Chloroquine

CTZ:

Clotrimazole

DAPK1:

Death associated protein kinase 1

DHA:

Dihydroartemisinin

Dppb:

1,4-Bis(diphenylphosphino)butane

Dppm:

Bis(diphenylphosphino) methane

DR5:

Death receptor 5

ER:

Endoplasmic reticulum

9-ETG:

9-Ethylguanine

ImN:

Imidazole

Lap:

Lapachol

Mebipy:

5,5-Dimethyl-2,20–bipyridine

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

Ph3P:

Triphenylphosphine

TEM:

Transmission electron microscopy

TgEF1-α:

T. gondii Elongation factor 1α

TNF:

Tumor necrosis factor

TRAF2:

TNF receptor associated factor 2

References

  • Allardyce, C. S., Dorcier, A., Scolaro, C., & Dyson, P. J. (2005). Development of organometallic (organo-transition metal) pharmaceuticals. Applied Organometallic Chemistry, 19(1), 1–10.

    Article  CAS  Google Scholar 

  • Anghel, N., Müller, J., Serricchio, M., Jelk, J., Bütikofer, P., Boubaker, G., Imhof, D., Ramseier, J., Desiatkina, O., Păunescu, E., & Braga-Lagache, S. (2021). Cellular and molecular targets of nucleotide-tagged trithiolato-bridged arene ruthenium complexes in the protozoan parasites Toxoplasma gondii and Trypanosoma brucei. International Journal of Molecular Sciences, 22(19), 10787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anthony, E. J., Bolitho, E. M., Bridgewater, H. E., Carter, O. W., Donnelly, J. M., Imberti, C., Lant, E. C., Lermyte, F., Needham, R. J., Palau, M., & Sadler, P. J. (2020). Metallodrugs are unique: Opportunities and challenges of discovery and development. Chemical Science, 11(48), 12888–12917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barbosa, M. I., Correa, R. S., de Oliveira, K. M., Rodrigues, C., Ellena, J., Nascimento, O. R., Rocha, V. P., Nonato, F. R., Macedo, T. S., Barbosa-Filho, J. M., & Soares, M. B. (2014). Antiparasitic activities of novel ruthenium/lapachol complexes. Journal of Inorganic Biochemistry, 136, 33–39.

    Article  CAS  PubMed  Google Scholar 

  • Barna, F., Debache, K., Vock, C. A., Küster, T., & Hemphill, A. (2013). In vitro effects of novel ruthenium complexes in Neospora caninum and Toxoplasma gondii tachyzoites. Antimicrobial Agents and Chemotherapy, 57(11), 5747–5754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basto, A. P., Anghel, N., Rubbiani, R., Müller, J., Stibal, D., Giannini, F., Süss-Fink, G., Balmer, V., Gasser, G., Furrer, J., & Hemphill, A. (2019). Targeting of the mitochondrion by dinuclear thiolato-bridged arene ruthenium complexes in cancer cells and in the apicomplexan parasite Neospora caninum. Metallomics, 11(2), 462–474.

    Article  CAS  PubMed  Google Scholar 

  • Basto, A. P., Müller, J., Rubbiani, R., Stibal, D., Giannini, F., Süss-Fink, G., Balmer, V., Hemphill, A., Gasser, G., & Furrer, J. (2017). Characterization of the activities of dinuclear thiolato-bridged arene ruthenium complexes against Toxoplasma gondii. Antimicrobial Agents and Chemotherapy, 61(9), 10–1128.

    Article  Google Scholar 

  • Bastos, T. M., Barbosa, M. I., da Silva, M. M., da C. Júnior, J. W., Meira, C. S., Guimaraes, E. T., Ellena, J., Moreira, D. R., Batista, A. A., & Soares, M. B. (2014). Nitro/nitrosyl-ruthenium complexes are potent and selective anti-Trypanosoma cruzi agents causing autophagy and necrotic parasite death. Antimicrobial Agents and Chemotherapy, 58(10), 6044–6055.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bern, C., Kjos, S., Yabsley, M. J., & Montgomery, S. P. (2011). Trypanosoma cruzi and Chagas’ disease in the United States. Clinical Microbiology Reviews, 24(4), 655–681.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cavalli, A., & Bolognesi, M. L. (2009). Neglected tropical diseases: Multi-target-directed ligands in the search for novel lead candidates against Trypanosoma and Leishmania. Journal of Medicinal Chemistry, 52(23), 7339–7359.

    Article  CAS  PubMed  Google Scholar 

  • Chellan, P., Land, K. M., Shokar, A., Au, A., An, S. H., Taylor, D., Smith, P. J., Chibale, K., & Smith, G. S. (2013). Di-and trinuclear ruthenium-, rhodium-, and iridium-functionalized pyridyl aromatic ethers: A new class of antiparasitic agents. Organometallics, 32(17), 4793–4804.

    Article  CAS  Google Scholar 

  • Chen, H., Parkinson, J. A., Morris, R. E., & Sadler, P. J. (2003). Highly selective binding of organometallic ruthenium ethylenediamine complexes to nucleic acids: Novel recognition mechanisms. Journal of the American Chemical Society, 125(1), 173–186.

    Article  CAS  PubMed  Google Scholar 

  • Claudel, M., Schwarte, J. V., & Fromm, K. M. (2020). New antimicrobial strategies based on metal complexes. Chemistry, 2(4), 849–899.

    Article  CAS  Google Scholar 

  • Coppens, I. (2014). Exploitation of auxotrophies and metabolic defects in Toxoplasma as therapeutic approaches. International Journal for Parasitology, 44(2), 109–120.

    Article  CAS  PubMed  Google Scholar 

  • Costa, M. S., Gonçalves, Y. G., Teixeira, S. C., de Oliveira Nunes, D. C., Lopes, D. S., da Silva, C. V., da Silva, M. S., Borges, B. C., Silva, M. J. B., Rodrigues, R. S., & de Melo Rodrigues, V. (2019). Increased ROS generation causes apoptosis-like death: Mechanistic insights into the anti-Leishmania activity of a potent ruthenium (II) complex. Journal of Inorganic Biochemistry, 195, 1–12.

    Article  CAS  PubMed  Google Scholar 

  • Critical Appraisal Skills Programme (2018). CASP (Systematic Review) Checklist. [online] Available at: https://casp-uk.net/casp-tools-checklists/. Accessed: 20th July, 2023.

  • Demoro, B., Rossi, M., Caruso, F., Liebowitz, D., Olea-Azar, C., Kemmerling, U., Maya, J. D., Guiset, H., Moreno, V., Pizzo, C., & Mahler, G. (2013). Potential mechanism of the anti-trypanosomal activity of organoruthenium complexes with bioactive thiosemicarbazones. Biological Trace Element Research, 153, 371–381.

    Article  CAS  PubMed  Google Scholar 

  • Den Boer, M., Argaw, D., Jannin, J., & Alvar, J. (2011). Leishmaniasis impact and treatment access. Clinical Microbiology and Infection, 17(10), 1471–1477.

    Article  Google Scholar 

  • Dubey, J. P. (2021). Toxoplasmosis of animals and humans. CRC Press.

    Book  Google Scholar 

  • Dubey, J. P., & Lindsay, D. S. (1996). A Review of Neospora caninum and Neosporosis. Veterinary Parasitology, 67(1–2), 1–59.

    Article  CAS  PubMed  Google Scholar 

  • Farrell, N. P., Williamson, J., & McLaren, D. J. (1984). Trypanocidal and antitumour activity of platinum-metal and platinum-metal-drug dual-function complexes. Biochemical Pharmacology, 33(7), 961–971.

    Article  CAS  PubMed  Google Scholar 

  • Flocke, L. S., Trondl, R., Jakupec, M. A., & Keppler, B. K. (2016). Molecular mode of action of NKP-1339–a clinically investigated ruthenium-based drug–involves ER-and ROS-related effects in colon carcinoma cell lines. Investigational New Drugs, 34, 261–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gambino, D. (2011). Potentiality of vanadium compounds as anti-parasitic agents. Coordination Chemistry Reviews, 255(19–20), 2193–2203.

    Article  CAS  Google Scholar 

  • Gambino, D., & Otero, L. (2012). Perspectives on what ruthenium-based compounds could offer in the development of potential antiparasitic drugs. Inorganica Chimica Acta, 393, 103–114.

    Article  CAS  Google Scholar 

  • Gasser, G., Ott, I., & Metzler-Nolte, N. (2011). Organometallic anticancer compounds. Journal of Medicinal Chemistry, 54(1), 3–25.

    Article  CAS  PubMed  Google Scholar 

  • Giordani, F., Morrison, L. J., Rowan, T. G., De Koning, H. P., & Barrett, M. P. (2016). The animal trypanosomiases and their chemotherapy: A review. Parasitology, 143(14), 1862–1889.

    Article  PubMed  Google Scholar 

  • Grant, M. J., & Booth, A. (2009). A typology of reviews: An analysis of 14 review types and associated methodologies. Health Information and Libraries Journal, 26(2), 91–108.

    Article  PubMed  Google Scholar 

  • Han Ang, W., & Dyson, P. J. (2006). Classical and non-classical ruthenium-based anticancer drugs: Towards targeted chemotherapy. European Journal of Inorganic Chemistry, 2006(20), 4003–4018.

    Article  Google Scholar 

  • Hartinger, C. G., Jakupec, M. A., Zorbas-Seifried, S., Groessl, M., Egger, A., Berger, W., Zorbas, H., Dyson, P. J., & Keppler, B. K. (2008). KP1019, a new redox-active anticancer agent–Preclinical development and results of a clinical phase I study in tumor patients. Chemistry & Biodiversity, 5(10), 2140–2155.

    Article  CAS  Google Scholar 

  • Hess, J., Keiser, J., & Gasser, G. (2015). Toward organometallic antischistosomal drug candidates. Future Medicinal Chemistry, 7(6), 821–830.

    Article  CAS  PubMed  Google Scholar 

  • Hotez, P. J., Bottazzi, M. E., Franco-Paredes, C., Ault, S. K., & Periago, M. R. (2008). The neglected tropical diseases of Latin America and the Caribbean: A review of disease burden and distribution and a roadmap for control and elimination. PLoS Neglected Tropical Diseases, 2(9), e300.

    Article  PubMed  PubMed Central  Google Scholar 

  • Iniguez, E., Sánchez, A., Vasquez, M. A., Martínez, A., Olivas, J., Sattler, A., Sánchez-Delgado, R. A., & Maldonado, R. A. (2013). Metal–drug synergy: New ruthenium (II) complexes of ketoconazole are highly active against Leishmania major and Trypanosoma cruzi and nontoxic to human or murine normal cells. JBIC Journal of Biological Inorganic Chemistry, 18, 779–790.

    Article  CAS  PubMed  Google Scholar 

  • Iniguez, E., Varela-Ramirez, A., Martínez, A., Torres, C. L., Sánchez-Delgado, R. A., & Maldonado, R. A. (2016). Ruthenium-Clotrimazole complex has significant efficacy in the murine model of cutaneous leishmaniasis. Acta Tropica, 164, 402–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Innes, E. A., Bartley, P. M., Maley, S. W., Wright, S. E., & Buxton, D. (2007). Comparative host–parasite relationships in ovine toxoplasmosis and bovine neosporosis and strategies for vaccination. Vaccine, 25(30), 5495–5503.

    Article  CAS  PubMed  Google Scholar 

  • Jelk, J., Balmer, V., Stibal, D., Giannini, F., Süss-Fink, G., Bütikofer, P., Furrer, J., & Hemphill, A. (2019). Anti-parasitic dinuclear thiolato-bridged arene ruthenium complexes alter the mitochondrial ultrastructure and membrane potential in Trypanosoma brucei bloodstream forms. Experimental Parasitology, 205, 107753.

    Article  CAS  PubMed  Google Scholar 

  • Keogan, D. M., & Griffith, D. M. (2014). Current and potential applications of bismuth-based drugs. Molecules, 19(9), 15258–15297.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kirchhoff, L. V. (2011). Epidemiology of American trypanosomiasis (Chagas disease). Advances in Parasitology, 75, 1–18.

    Article  PubMed  Google Scholar 

  • Klinkert, M. Q., & Heussler, V. (2006). The use of anticancer drugs in antiparasitic chemotherapy. Mini Reviews in Medicinal Chemistry, 6(2), 131–143.

    Article  CAS  PubMed  Google Scholar 

  • Küster, T., Lense, N., Barna, F., Hemphill, A., Kindermann, M. K., Heinicke, J. W., & Vock, C. A. (2012). A new promising application for highly cytotoxic metal compounds: η6-areneruthenium (II) phosphite complexes for the treatment of alveolar echinococcosis. Journal of Medicinal Chemistry, 55(9), 4178–4188.

    Article  PubMed  Google Scholar 

  • Le Loup, G., Pialoux, G., & Lescure, F. X. (2011). Update in treatment of Chagas disease. Current Opinion in Infectious Diseases, 24(5), 428–434.

    Article  PubMed  Google Scholar 

  • Li, F., Collins, J. G., & Keene, F. R. (2015). Ruthenium complexes as antimicrobial agents. Chemical Society Reviews, 44(8), 2529–2542.

    Article  CAS  PubMed  Google Scholar 

  • Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Annals of Internal Medicine, 151(4), W-65.

    Article  Google Scholar 

  • Lüder, C. G., Stanway, R. R., Chaussepied, M., Langsley, G., & Heussler, V. T. (2009). Intracellular survival of apicomplexan parasites and host cell modification. International Journal for Parasitology, 39(2), 163–173.

    Article  PubMed  Google Scholar 

  • Macedo, T. S., Colina-Vegas, L., Da Paixao, M., Navarro, M., Barreto, B. C., Oliveira, P. C., Macambira, S. G., Machado, M., Prudencio, M., D’Alessandro, S. A. R. A. H., & Basilico, N. (2016). Chloroquine-containing organoruthenium complexes are fast-acting multistage antimalarial agents. Parasitology, 143(12), 1543–1556.

    Article  CAS  PubMed  Google Scholar 

  • Martínez, A., Carreon, T., Iniguez, E., Anzellotti, A., Sánchez, A., Tyan, M., Sattler, A., Herrera, L., Maldonado, R. A., & Sánchez-Delgado, R. A. (2012). Searching for new chemotherapies for tropical diseases: Ruthenium–clotrimazole complexes display high in vitro activity against Leishmania major and Trypanosoma cruzi and low toxicity toward normal mammalian cells. Journal of Medicinal Chemistry, 55(8), 3867–3877.

    Article  PubMed  PubMed Central  Google Scholar 

  • Martínez, A., Rajapakse, C. S., Naoulou, B., Kopkalli, Y., Davenport, L., & Sánchez-Delgado, R. A. (2008). The mechanism of antimalarial action of the ruthenium (II)–chloroquine complex [RuCl2(CQ)]2. JBIC Journal of Biological Inorganic Chemistry, 13, 703–712.

    Article  PubMed  Google Scholar 

  • Milne, G., Webster, J. P., & Walker, M. (2020). Toxoplasma gondii: An underestimated threat? Trends in Parasitology, 36(12), 959–969.

    Article  PubMed  Google Scholar 

  • Mishra, H., & Mukherjee, R. (2006). Half-sandwich η6-benzene Ru (II) complexes of pyridylpyrazole and pyridylimidazole ligands: Synthesis, spectra, and structure. Journal of Organometallic Chemistry, 691(16), 3545–3555.

    Article  CAS  Google Scholar 

  • Morrison, C. N., Prosser, K. E., Stokes, R. W., Cordes, A., Metzler-Nolte, N., & Cohen, S. M. (2020). Expanding medicinal chemistry into 3D space: Metallofragments as 3D scaffolds for fragment-based drug discovery. Chemical Science, 11(5), 1216–1225.

    Article  CAS  Google Scholar 

  • Munteanu, A. C., & Uivarosi, V. (2021). Ruthenium complexes in the fight against pathogenic microorganisms. An extensive review. Pharmaceutics, 13(6), 874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nyawade, E. A., Friedrich, H. B., & Omondi, B. (2014). Synthesis, characterisation and crystal structures of new water-soluble 1-alkanaminedicarbonyl (η5-cyclopentadienyl) ruthenium (II) tetrafluoroborate complex salts. Inorganica Chimica Acta, 415, 44–51.

    Article  CAS  Google Scholar 

  • Priest, J. W., & Hajduk, S. L. (1994). Developmental regulation of mitochondrial biogenesis in Trypanosoma brucei. Journal of Bioenergetics and Biomembranes, 26, 179–191.

    Article  CAS  PubMed  Google Scholar 

  • Rademaker-Lakhai, J. M., Van Den Bongard, D., Pluim, D., Beijnen, J. H., & Schellens, J. H. (2004). A phase I and pharmacological study with imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a novel ruthenium anticancer agent. Clinical Cancer Research, 10(11), 3717–3727.

    Article  CAS  PubMed  Google Scholar 

  • Rivera, G., Bocanegra-García, V., Ordaz-Pichardo, C., Nogueda-Torres, B., & Monge, A. (2009). New therapeutic targets for drug design against Trypanosoma cruzi, advances and perspectives. Current Medicinal Chemistry, 16(25), 3286–3293.

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez Arce, E., Sarniguet, C., Moraes, T. S., Vieites, M., Tomaz, A. I., Medeiros, A., Comini, M. A., Varela, J., Cerecetto, H., Gonzalez, M., & Marques, F. (2015). A new ruthenium cyclopentadienyl azole compound with activity on tumor cell lines and trypanosomatid parasites. Journal of Coordination Chemistry, 68(16), 2923–2937.

    Article  CAS  Google Scholar 

  • Schmunis, G. A. (2007). Epidemiology of Chagas disease in non endemic countries: The role of international migration. Memórias Do Instituto Oswaldo Cruz, 102, 75–86.

    Article  PubMed  Google Scholar 

  • Serrano-Ruiz, M., Lorenzo-Luis, P., & Romerosa, A. (2017). Easy synthesis and water solubility of ruthenium complexes containing PPh3, mTPPMS, PTA and mPTA,(mTPPMS= meta-triphenyphosphine monosulfonate, PTA= 1, 3, 5-triaza-7-phosphaadamantane, mPTA= N-methyl-1, 3, 5-triaza-7-phosphaadamantane). Inorganica Chimica Acta, 455, 528–534.

    Article  CAS  Google Scholar 

  • Silva, J. J. N., Guedes, P. M. M., Zottis, A., Balliano, T. L., Nascimento Silva, F. O., Franca Lopes, L. G., Ellena, J., Oliva, G., Andricopulo, A. D., Franco, D. W., & Silva, J. S. (2010). Novel ruthenium complexes as potential drugs for Chagas’s disease: Enzyme inhibition and in vitro/in vivo trypanocidal activity. British Journal of Pharmacology, 160(2), 260–269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silva, J. J. N., Osakabe, A. L., Pavanelli, W. R., Silva, J. S., & Franco, D. W. (2007). In vitro and in vivo antiproliferative and trypanocidal activities of ruthenium NO donors. British Journal of Pharmacology, 152(1), 112–121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silva, J. J. N., Pavanelli, W. R., Pereira, J. C. M., Silva, J. S., & Franco, D. W. (2009). Experimental chemotherapy against Trypanosoma cruzi infection using ruthenium nitric oxide donors. Antimicrobial Agents and Chemotherapy, 53(10), 4414–4421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith, N. C., Goulart, C., Hayward, J. A., Kupz, A., & Miller, C. M. (2021). van Dooren GCJIjfp. Control of human toxoplasmosis. International Journal of Parasitology, 51, 95–121.

    Article  CAS  PubMed  Google Scholar 

  • Snow, R. W. (2015). Global malaria eradication and the importance of Plasmodium falciparum epidemiology in Africa. BMC Medicine, 13(1), 1–3.

    Article  Google Scholar 

  • Trondl, R., Heffeter, P., Kowol, C. R., Jakupec, M. A., Berger, W., & Keppler, B. K. (2014). NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application. Chemical Science, 5(8), 2925–2932.

    Article  CAS  Google Scholar 

  • WHO Expert Committee on the Control of Chagas Disease, World Health Organization. (2002). Control of Chagas disease: Second report of the WHO Expert Committee. World Health Organization.

  • Zeng, L., Gupta, P., Chen, Y., Wang, E., Ji, L., Chao, H., & Chen, Z. S. (2017). The development of anticancer ruthenium (II) complexes: From single molecule compounds to nanomaterials. Chemical Society Reviews, 46(19), 5771–5804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge Ramakrishna Mission Vidyamandira, Belur Math for providing the necessary requirements in drafting this review.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Zoology, Ramakrishna Mission Vidyamandira, Belur Math, Howrah, 711202, India

    Shibam Chakraborty, Sumit Ghosh, Shauryabrota Dalui & Avijit Dey

  2. Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India

    Sumit Ghosh

  3. Department of Zoology, Immunology Lab, Ballygunge Science College, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India

    Shauryabrota Dalui

Authors
  1. Shibam Chakraborty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sumit Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shauryabrota Dalui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Avijit Dey
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SC was contributed to conceptualization, methodology, data curation, writing—original draft, visualization, investigation, validation, writing—review and editing, formal analysis. SG was contributed to visualization, investigation, data curation, validation, writing—review and editing, formal analysis. SD was contributed to visualization, investigation, data curation, validation, writing—review and editing. AD was contributed to conceptualization, methodology, data curation, writing—original draft, supervision, writing—review and editing.

Corresponding author

Correspondence to Avijit Dey.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors share no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chakraborty, S., Ghosh, S., Dalui, S. et al. A review on the anti-parasitic activity of ruthenium compounds. JoBAZ 85, 17 (2024). https://doi.org/10.1186/s41936-024-00371-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s41936-024-00371-z

Keywords