Organometallics in Medicinal Chemistry: Antiparasitic Agents

Abstract

Neglected tropical diseases (NTDs) encompass a diverse group of 20 medical conditions triggered by various pathogens, including viruses, bacteria, protozoa, and parasitic worms. Diseases caused by parasitic protozoa and parasitic worms show the highest incidence worldwide. NTDs predominantly afflict impoverished communities in tropical regions, although some exhibit a broader geographic reach. It is estimated that over 1 billion people suffer from NTDs, spanning 149 countries. Additionally, malaria is caused by protozoa of the genus Plasmodium and is highly prevalent in similar geographic regions. New drugs are urgently needed for the treatment of these diseases. In the last decades, various research groups have endeavored to develop organometallic compounds with potential applications as drugs against malaria and NTDs diseases caused by trypanosomatid parasites and parasitic helminths. This perspective highlights selected efforts from these groups in the pursuit of innovative therapeutic solutions. Relevant bioorganometallic compounds belonging to the typical classes of metallocenes, “half sandwich” M-arenes and metal carbonyls will be particularly described.

Keywords:
organometallics; neglected diseases; malaria; trypanosomatid parasites; parasitic helminths

1. Introduction

Although human life relies on at least ten essential metals, more than forty non-essential metals, including radionuclides, currently find different applications in therapy and diagnostics.¹, ² Classical Inorganic Medicinal Chemistry involves five main research areas (Figure 1): chelation therapy that looks for designing proper ligands to remove excess of metals causing disease, supplementation of essential metals that are present in vivo in deficient levels causing disease, development of contrast agents mainly as tools for magnetic resonance imaging (MRI) diagnostics, radiopharmaceuticals for diagnosis or therapy and the wider area of development of therapeutic agents for the treatment of varied diseases.

Figure 1
Main classical areas of Inorganic Medicinal Chemistry.

The later aims to design, identify and prepare new metal-based drugs or prospective drugs. Additionally, it includes the study of the chemical changes that these compounds suffer in the biological media, the unraveling of their mechanism of action at molecular level and the establishment of structure activity relationships that could guide in the drug discovery process. Recently, this area is paying increasing attention to metallomics as the comprehensive analysis of the metal species within a cell or tissue type relevant to the unveiling of the mechanism of action.³

Although therapeutical properties of metals and metal compounds for the treatment of different pathologies have been known since ancient times, the serendipity discovery of the antineoplastic properties of the very simple cisplatin compound in 1965 (Figure 2) led to the explosive development of the modern era of Medicinal Inorganic Chemistry, which is marked by the rational design of new compounds searching for selected therapeutical properties not restricted to antitumoral activity.⁴

Figure 2
Structure of cisplatin (c¿s-diamminedichloroplatinum(II)).

Novel metal-based compounds are being currently investigated against viruses, parasites, bacteria and fungi and diseases such as diabetes, Parkinson and Alzheimer, among others. Different metal compounds have been approved by different pharmacopeias for clinical use and are daily used in medicine. Many others are in drug development advanced clinical phases waiting for entering the pharmaceutical market in the next years. Multitude of prospective metallodrugs has been explored for their potential as anticancer agents, antimicrobials, antivirals, and various other indications. Despite this extensive investigation, only a limited number of metal compounds have been successfully translated into clinical applications.¹, ⁵, ⁶ A detailed list of medicines including a metal can be found in the supplementary file of Anthony et al.¹ Most common examples in this list are some simple metallic salts, like lithium carbonate, silver sulfadiazine, bismuth subcitrate potassium and magnesium sulfate or classical coordination compounds, like cisplatin, oxaliplatin, carboplatin, sodium nitroprusside, cyanocobalamin, ibritumomab tiuxetan, glucantime, pentostam, auranofin and Sm-153 lexidronam.

In modern era this discipline has left behind serendipity and involves a rational design of new drugs based on Inorganic Chemistry knowledge. The chemical characteristics associated with both the central metal (oxidation state, acidity, geometry, coordination number, kinetic and thermodynamic stability, among others) and the ligand (basicity, donor atoms, denticity, hapticity, chirality, reactivity in biological environments) are of particular importance for this design. If all these aspects are considered, metal compounds offer broad possibilities for designing potentially bioactive compounds. Furthermore, considering that many of these compounds may undergo redox reactions of the central metal ion, ligand substitution reactions, or reactions at the level of organic ligands in biological environments, they can effectively serve as prodrugs that will be activated in vivo. In this sense, metal compounds offer a wider range of possibilities compared to organic compounds developed by Medicinal Organic Chemistry. This poses a challenge in both the design of potential metal-based drugs and the elucidation of their mechanism of action. As the pursuit of innovative and improved drugs becomes increasingly pressing, the existing drug discovery and development pipelines designed for organic drugs, relying on target identification or high-throughput screening of libraries of compounds, prove to be less effective when applied to metallodrugs. Metal-based drugs or prospective metal-based drugs include simple metal salts, classical coordination compounds and organometallic compounds.

2. Bioorganometallics

At the end of the 20^th century, it was demonstrated that organometallic compounds usually used in catalysis could themselves be used to treat diseases. In this context, Bioorganometallic Chemistry is a relatively recent and deeply interdisciplinary field, focusing on authentic organometallic compounds featuring at least one σ metal-carbon bond, with relevance in a biological context. This area was described as such for the first time more than 20 years ago by the pioneer French researcher Gerard Jaouen.⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³ Specifically, it encompasses organometallic drugs and prospective organometallic drugs. These compounds provide a promising and innovative approach to designing new drugs with unique modes of action, offering distinct advantages compared to traditional coordination compounds and purely organic substances. Notably, these advantages include highly diverse structural possibilities, the ability to modulate their lability to achieve kinetically stable compounds, a lipophilic nature that could favor the in vivo behavior, and a rich redox chemistry. Although the primary focus of the field has been on the development of potential anticancer drugs, attempts to expand generating bioactive compounds for other purposes have been successful.¹⁰, ¹¹, ¹², ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹

Figure 3 shows the main types of organometallic compounds investigated in Medicinal Chemistry during the last decades: metallocenes, metal-arenes (M-arenes), metal-carbonyls (M-carbonyls) and metal-carbenes (M-carbenes).⁶

Figure 3
Main types of organometallics investigated in Medicinal Chemistry.

Organometallic compounds of these primary categories emerged as alternative chemotherapeutic agents against tumors, pathogenic fungi and bacteria and viruses, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thanks to their distinct and specific physicochemical properties.⁶, ⁹, ¹¹, ¹⁴, ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶, ²⁷

Metallocenes consist of two cyclopentadiene (Cp) anions that exhibit a robust binding to certain metals such as iron, adopting a side-on orientation. Due to this typical configuration, these compounds are frequently referred to as “sandwich complexes” due to the manner in which the Cp ligands envelop the metal ion.

Demonstrating broad antitumor activity, titanocene dichloride became the first non-platinum complex to undergo clinical trials for its potential use as a chemotherapy drug (Figure 4).²⁸ A quite different mechanism of action to that of cisplatin was proposed for it involving the binding to transferrin which transports it to tumor cells that usually show overexpressed receptors of this protein due to high iron requirements. After preferentially entering into the tumor cells, Ti^IV accumulates in nucleic acids rich regions probably generating a deoxyribonucleic acid (DNA) adduct by binding to the phosphate skeleton of this biomolecule.²⁹ Reaching phase II in Germany, trials were later on abandoned due to the uncontrolled and complex hydrolysis of the compound in biological medium that complicated its pharmacokinetic study and the characterization of its active metabolite, among other drawbacks.

Figure 4
Structures of titanocene dichloride, ferrocene, tamoxifen and its biological active species hydroxy-tamoxifen and the analogous organometallic compound ferrocifen.

Among metallocenes, the ferrocene moiety has undoubtedly played a pivotal role in the advancement of bioorganometallic drugs, showcasing several physicochemical advantages tailored for this purpose (Figure 4). It boasts affordability, easy derivatization, stability in aqueous solutions under aerobic conditions, high lipophilicity, and non-cytotoxicity. Furthermore, it possesses the capability to generate reactive oxygen species (ROS) through Fenton-like reactions, adding an additional mechanism of action. Considering these advantages, the integration of the ferrocene moiety into organic drugs has emerged as a successful strategy to reduce cytotoxicity in normal cells and enhance the therapeutic index of such drugs. Consequently, a long series of antitumor ferrocenyl compounds, exemplified by ferrocifen, the organometallic analogue of the anticancer drug tamoxifen developed by the French group headed by Jaouen,³⁰, ³¹ has been successfully developed (Figure 4). First reported in 1996,³² ferrocifen stands out as one of the earliest organometallic selective estrogen receptor modulators. The inclusion of the ferrocenyl moiety into the organic drug resulted in enhanced activity compared to the parent drug and in a broader spectrum of activity. Notably, it exhibits antiproliferative effects on both hormone-dependent (MCF-7) and hormone-independent (MDA-MB-231) breast cancer cells with significant efficacy. In contrast, tamoxifen demonstrates antiestrogenic activity exclusively in hormone-dependent MCF-7 breast cancer cells. Ferrocifen has been in pre-clinical studies as antitumoral agent. Cell death mechanism induced by ferrocifen and its derivatives differs depending on structure, cell line and concentration. Generation of ROS through Fenton reaction and effects on thioredoxine reductase have been described as part of it. Ferrocifen is highly insoluble in water and requires a formulation stage before being administered in vivo. Lipid nanocapsules including ferrocifen are currently ol. 2023, 53, 411. [https://doi.org/10.1016/j.ijpara.2022.10.006

The same strategy was followed by Jaouen and co-workers³¹, ³⁴ to get more than 200 ferrocenyl derivatives with antitumoral activity, perform structure activity relationships (SAR) studies and make attempts to unravel the mechanism of action. Other groups³³ have also adopted the strategy of generation of ferrocene-containing hybrids of different organic drugs to get compounds with a diversity of activities.

Half sandwich ruthenium arenes have been by far the most studied M-arenes in organometallic medicinal chemistry. This type of organometallic compounds (Figure 5) offers ample possibilities for designing new compounds by incorporating a range of ligands X, Y and Z, different arene types (cyclopentadienyl or aryl and substituted) or functional groups onto the arene moiety. These modifications have the capability to influence the physicochemical and biological characteristics of the compounds, leading to a diverse array of mechanisms of action.⁶, ¹⁶

Figure 5
General structure of Ru^II-arene half sandwich (piano stool) complexes (right) and main examples of compounds entering clinical trials by Sadler’s (ONCO 4417)³⁵ and Dyson’s (RAPTA-C)³⁵, ³⁶ groups.

These “piano stool” shaped compounds exhibit the ability to covalently interact with guanine residues in DNA through the substitution of labile ligands and, additionally, by intercalating via selected expanded bicycle arene moieties, or minor groove binding. Two distinct families of anticancer compounds have undergone thorough investigation in the last decades: Ru-arene compounds [Ru(η⁶-arene)(en)(Cl)]+, where en = ethylenediamine, and the RAPTA series of complexes ([Ru(η⁶-arene)(PTA)(Cl)₂]), with PTA = 1,3,5-triaza-7-phosphoadamantane. These compounds have demonstrated significant efficacy in both primary tumors or metastasis, leading to the selection of certain candidates for further in vivo studies. Selected compounds that have entered clinical trials as antitumorals are shown in Figure 5.¹²

Although osmium and iridium half-sandwich complexes have not garnered as much focus as their ruthenium counterparts in terms of their potential applications in medicinal chemistry, considerable research has been conducted to investigate the therapeutic potential, biological properties, and mechanisms of action of these complexes.³⁷, ³⁸, ³⁹, ⁴⁰, ⁴¹

Within metal-carbonyls, rhenium(I) tricarbonyls have demonstrated the most encouraging antitumoral outcomes. The prevalent structural motif of Re utilized in biological systems is the stable Re^I tricarbonyl core (Figure 6). These organometallic compounds exhibit several intrinsic properties that are advantageous for the development of innovative anti-cancer drug candidates. Moreover, their straightforward synthesis enables the generation of a diverse array of compounds, allowing for the tuning of properties to optimize biological activity.

Figure 6
Rhenium(I) tricarbonyls common structure: X monodentate ligand, YZ bidentate ligand.⁴¹, ⁴⁴

Additionally, leveraging their rich spectroscopic properties these compounds have also been utilized for in vitro in cell fluorescence and vibrational microscopic imaging. The French group headed by Policar⁴⁵, ⁴⁶, ⁴⁷ has developed front-line research in this sense.

Concerning the main types of organometallics explored in Medicinal Chemistry (Figure 3), metal-N-heterocyclic carbenes have demonstrated notably robust antitumoral activity, particularly those of gold. Casini and co-workers⁴⁸ have extensively worked on the topic.

While the primary emphasis in bioorganometallic research has traditionally centered on the development of antitumor agents, the advent of the SARS-CoV-2 pandemic has prompted several research groups to redirect their focus toward viral infections. Although this area has been relatively underexplored in terms of metal-based bioactive compounds, an expanding body of reports²⁶, ⁴⁹, ⁵⁰, ⁵¹, ⁵², ⁵³, ⁵⁴, ⁵⁵ detailing metal complexes exhibiting activity in SARS-CoV-2 infection models affirms the potential efficacy of metal complexes in this particular area. In particular, Ott and co-workers⁵⁶, ⁵⁷ together with other organometallic groups²⁶ have recently reported on gold and silver N-heterocyclic carbene complexes with antiviral effects against SARS-CoV-2 in infected cells as potent inhibitors of the SARS-CoV-2 papain-like protease PLpro, which is a key enzyme in the virus replication in infected cells.

Having delineated the most relevant medicinal chemistry applications of the main classes of organometallics, this perspective will focus on the major strides made in the advancement of therapeutic organometallic antiparasitic agents over the past three decades, not providing a comprehensive or exhaustive review. The pioneering work performed by selected leading and representative groups for the development of agents against highly prevalent parasitic diseases, like malaria and diseases caused by trypanosomatid parasites and parasitic helminths, are highlighted. Outcomes by those groups having done efforts to modify structures through rational design, to get at least qualitative structure-activity relationships and to identify molecular targets and mode of action are emphasized.

2.1. Organometallics as antiparasitic compounds

Neglected tropical diseases (NTDs) encompass a diverse group of 20 medical conditions triggered by various pathogens, including viruses, bacteria, protozoa, and parasitic worms. NTDs predominantly afflict impoverished communities in tropical regions, although some exhibit a broader geographic reach. It is estimated that over 1 billion people suffer from NTDs, spanning 149 countries. The epidemiology of these diseases is intricate, often intertwined with environmental factors. Many are vector-borne, involve animal reservoirs, and entail complex life cycles, rendering public health control challenging. NTDs disproportionately impact already vulnerable populations, whether due to poverty, marginalization, geographic location, or living conditions, leading to considerable suffering, disability, and death and posing severe health and economic challenges. The majority of drugs used against NTDs are old and frequently yield undesired side effects. Regrettably, major pharmaceutical companies exhibit limited interest in developing new drug candidates or vaccines for NTDs. Despite the substantial size of the target population, it is primarily situated in developing countries with low socioeconomic status, making them unable to afford expensive medicines. Consequently, much of the research on NTDs is conducted by academia, open sources, and nonprofit organizations.⁵⁸, ⁵⁹, ⁶⁰, ⁶¹

On the other hand, PLoS Neglected Tropical Diseases,⁶¹ in alignment with the World Health Organization (WHO)⁶² and several other international agencies, does not classify malaria produced by Plasmodium falciparum as an NTD because much attention has been put on it by the pharmaceutical industry and the health authorities. Accordingly, the P. falciparum caused malaria disease does not fulfill the definition of NTD. Transmission occurs through the bites of infected female Anopheles mosquitoes. In 2022, the Medicines for Malaria Venture⁶³ documented 249 million cases of malaria, reflecting a rise of 5 million compared to 2021. This increase was attributed to various factors, including severe weather events, population expansion, and conflict-driven forced migration. Notably, 76% of malaria-related deaths worldwide occurred in children under the age of 5. Malaria in humans is caused by four Plasmodium species: P. falciparum, P. vivax, P. malariae, and P. ovae. Its prevalence is particularly pronounced in tropical and subtropical regions, with the African Region carrying the predominant burden of both cases and fatalities. The majority of instances in this region can be attributed to the Plasmodium falciparum parasite. Despite being preventable and treatable, timely diagnosis and effective treatment are essential. Failure to address an uncomplicated malaria case promptly can result in the progression to a severe form of the disease, often leading to fatal outcomes without timely intervention. Artemisinin-based combination therapies emerge as the most efficacious antimalarial medications presently accessible and constitute the primary recommended treatment for Plasmodium falciparum malaria, the most lethal malaria parasite globally. They combine two active pharmaceuticals with distinct mechanisms of action, featuring derivatives of artemisinin and a complementary drug. Artemisinin element plays a pivotal role in reducing the parasite count during the initial days of treatment, while the companion drug focuses on eliminating the remaining parasites. Nevertheless, this strategy faces challenges such as drug interactions and drug resistance.

Various research groups have endeavored to develop organometallic compounds with potential applications as drugs against malaria and NTDs diseases caused by trypanosomatid parasites and parasitic helminths. This perspective highlights selected efforts from these groups in the pursuit of innovative therapeutic solutions.

2.2. Organometallic antimalarials

Many research groups⁶⁴, ⁶⁵, ⁶⁶ have developed novel organometallics as prospective antimalarials. In particular, the advantages demonstrated by the ferrocene scaffold for the development of bioorganometallic drugs, as outlined in the preceding section, have led to the successful incorporation of this moiety into organic drugs. This design strategy has paved the way for the development of ferrocenyl analogues of existing antimalarial drugs to improve antimalarial activity, reduce cytotoxicity in normal cells and enhance the therapeutic index of such drugs. Additionally, this modification can induce favorable alterations in the properties of the compounds, including changes in solubility, hydrophobicity, and lipophilicity.

The most notable and groundbreaking example has been the development by the Brocard and Biot French group⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰ of the ferrocenyl derivative of the antimalarial drug chloroquine, known as ferroquine (Figure 7). The ferrocene moiety was incorporated into the lateral side-chain of the chloroquine skeleton. Chloroquine (Figure 7) was initially introduced as a main antimalarial drug in 1945, owing to its affordability, ease of use, and potent antimalarial efficacy. However, widespread resistance among P. falciparum parasites led to the withdrawal of chloroquine from malaria treatment in the majority of malaria-endemic countries.⁷¹ In vitro, ferroquine exhibited noteworthy activity against both chloroquine-sensitive and chloroquine-resistant P. falciparum strains, with no discernible cytotoxic effects. Ferroquine is presently undergoing clinical development and completed phase II trials for the treatment of malaria. It is under development for addressing uncomplicated Plasmodium falciparum malaria, administered orally in capsule form.⁷², ⁷³, ⁷⁴

Figure 7
Structures of the antimalarial drug chloroquine and the organometallic analogue ferroquine (Biot-Brocard).⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰

Plasmodium parasite breaks down host hemoglobin in its digestive vacuole to obtain a nutrient supply. This process releases free heme, which is toxic to the parasite. Within the vacuole, the parasite detoxifies heme by converting it into hematin, ultimately forming the insoluble hemozoin, which is non-toxic to the parasite. Chloroquine accumulates in the parasite’s digestive vacuole, preventing the conversion of toxic heme into its harmless crystalline form, hemozoin. To achieve this, the drug crosses the host red cell membrane, as well as the membranes of the parasite and its digestive vacuole. Ferroquine also targets beta-hematin and inhibits hemozoin formation, but additionally induces the generation of reactive oxygen species as part of its antimalarial mechanism. The heightened activity observed in respect to chloroquine was demonstrated to be, among other factors, a consequence of the generation of these reactive oxygen species through the reversible ferrocene/ferrocenium redox couple. Moreover, the enhanced lipophilic profile of ferroquine contributes to the prolonged retention of the drug within the digestive vacuole of the parasite.⁷⁵, ⁷⁶

Following this success, a multitude of ferrocene-containing compounds exhibiting favorable pharmacological profiles have been developed for the treatment of malarial infections by the same group and others.⁶⁴, ⁶⁵, ⁶⁶

2.3 Organometallic agents against trypanosomatid parasites

Gambino and co-workers⁷⁷, ⁷⁸, ⁷⁹, ⁸⁰, ⁸¹, ⁸², ⁸³ has performed since more than 20 years ago pioneering work on the development of metal-based potential drugs against diseases caused by trypanosomatid parasites. The group has been particularly interested in the development of bioactive compounds for the treatment of Chagas disease or American trypanosomiasis. This is an ancient endemic disease in Latin America caused by the protozoan parasite Trypanosoma cruzi (T. cruzi). It is considered an NTD by WHO. In the endemic Latin-American countries, it is mainly transmitted to humans and other mammalian hosts by infected blood-sucking insects. The disease expanded to non-endemic regions due to migration of unknowingly infected people that transmit the disease by blood transfusion, organ transplants and from mother to child. T. cruzi cycles between four biologically and morphologically distinct stages. Metacyclic trypomastigotes, released in the feces during an insect’s blood meal, enter the mammalian host through skin wounds or mucosa and initiate invasion of surrounding cells. Following cell invasion, they undergo a transformation into amastigotes and undergo multiplication within the host cells. Subsequently, amastigotes differentiate into highly mobile infective trypomastigotes, which are released into the bloodstream upon cell lysis. These trypomastigotes can infect adjacent cells, invade various tissues, or be ingested by an insect vector, completing the cycle by transforming into the rapidly dividing non-infective epimastigote form in the insect’s gut.

The group’s design strategy for developing new compounds has involved metal coordination of various families of structurally related bioactive ligands, each exhibiting antiparasitic activity by themselves. Compounds are rationally designed by changing the bioactive ligands family, the metal center, its oxidation state and geometry, and by including adequate coligands to improve relevant biological properties. The group⁷⁷, ⁸², ⁸³ has explored numerous families of bioactive ligands, various metal centers, and even organometallic centers in their research endeavors (Figure 8). The aim of this strategy is to modulate physicochemical and biological properties of the bioactive ligands and to identify hit metal compounds that affect multiple targets in the parasite.

Figure 8
Different families of bioactive ligands used by Gambino group for the development of agents against trypanosomatid parasites: (a) 5-nitrofuryl thiosemicarbazones; (b) 3-aminoquinoxaline-2-carbonitrile N¹, N⁴-dioxide derivatives; (c) bisphosphonates; (d) 1,10-phenanthroline derivatives; (e) pyridine-2-thiolate-1-oxide (mpo); (f) tropolones; (g) azoles; (h) 8-hydroxyquinoline derivatives.

In more recent years the group extended the interest to two other diseases caused by trypanosomatid parasites: human African trypanosomiasis (HAT, caused by Trypanosoma brucei) and leishmaniasis (caused by more than 20 species of Leishmania). Both diseases are also included in the list of NTDs.⁶⁰, ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷ There are reasons for this expanded research interest. These diseases rank among the most significant neglected illnesses, posing an urgent health crisis in developing countries. They frequently coexist in different poor regions of the world, such as leishmaniasis and Chagas’ disease in South America and leishmaniasis and HAT in Africa, spreading worldwide due to human migration and globalization. Despite being highly life-threatening infections, the available chemotherapy remains old and deficient. While these trypanosomatid protozoan parasites exhibit significant differences, being transmitted by distinct insect vectors and causing clinically diverse human diseases, research⁸⁸, ⁸⁹, ⁹⁰, ⁹¹ has demonstrated noteworthy similarities in their biology. Specifically, these parasites share more than 6,100 closely related genes encoding proteins out of a total gene count ranging from 8,000 to 12,000. This opens avenues for strategically planning the development of broad-spectrum compounds that could be trypanosomatid-specific, impacting all three major parasites rather than targeting only one. Such an approach could result in drugs affecting common targets across various parasites. In summary, the current aim of the group is to develop broad spectrum drugs affecting multiple trypanosomatid parasites but multifunctional drugs that affect multiple targets in the same parasite.

In particular, Gambino group has ventured in the development of organometallic compounds against trypanosomatid parasites of the metallocene, metal-arene and metal-carbonyl classes (Figure 3). Eleven series of bioactive organometallic compounds were rationally designed, synthesized, characterized and evaluated on T. cruzi, T. brucei or both parasites. T. brucei brucei (nagana cattle disease was used as a parasite model for African trypanosomiasis). An insight into the probable mechanism of action of the compounds was also provided. Metallomics, proteomics and transcriptomics studies in T. cruzi were performed for the first time in this parasite to unravel the main pathways affected by prospective organometallic drugs. Hit compounds of all these new families of compounds were selected based on their IC₅₀ (half-maximal inhibitory concentration) and selectivity index values (SI = IC₅₀ mammalian cells/IC₅₀ parasite) (Table 1). Their structures are depicted in Figure 9.

Table 1
Hit organometallic compounds and their IC₅₀ (half-maximal inhibitory concentrations) and selectivity index values (SI). Free ligands are included for comparison

Compound	T. cruzi		T. brucei		Reference
	IC50 / µM	SI	IC50 / µM	SI
1, [RuII2(η6-p-cymene)2(TSC4-H)2]Cl2	8.7a	3c	0.5b		92,93
TSC4	22.7a	> 100c	> 100b	–	92,93
2, [RuIICp(PPh3)(TSC3-H)]	0.41a	> 49c	3.5b	> 6c	94
TSC3	18.5a	2c	17.0b	2c	92,93
3, [RuIICp(PPh3)2(CTZ)](CF3SO3)	0.25d	8c	0.6b	3c	95
CTZ	1.8d	31c	> 25b	< 2c	95
4, [RuCl(η6-p-cymene)(phendione)](PF6)	–	–	0.19b	169c	96
Phendione	–	–	0.018b	53c	96
5,fac-[ReI(CO)3Br(TSC5)]	2.01a	22e	–	–	97
TSC5	12.7a	3e	–	–	97
6,fac-[ReI(CO)3(tmp)(CTZ)](PF6)	0.61f	8.4g	–	–	98,99
CTZ	10.2f	3.6g	–	–	98,99
7, [Pd(mpo)(dppf)](PF6)	0.64h	39g	–	–	100,101
8, [Pt(mpo)(dppf)](PF6)	0.28h	18g	–	–	100,102
Na mpo	1.33h	–	–	–	100
9, [Pt(TSC3-H)(dppf)](PF6)	0.76a	> 66e	0.52b	> 56e	103
10, [Pt(trop)(dppf)](PF6)	–	–	2.1b	18c	104
Htrop	–	–	> 60b	ca. 1c	104
11, [Pd(8HQNO2-H)(dppf)](PF6)	–	–	0.33b	102c	105
8HQNO2	–	–	0.8b	38.9c	105
12, [Pt(8HQClI-H)(dppf)](PF6)	–	–	0.14b	48c	106
8HQClI	–	–	2.4b	16.2c	106
13, [Ru(8HQII-H)(dppf)(bipy)]Cl	–	–	0.13b	38c	107
8HQII	–	–	1.7b	29c	107

• ^aDm28c strain T. cruzi trypomastigotes; ^bbloodstream T. brucei brucei strain 427; ^cJ774 murine macrophages; ^dY strain T. cruzi epimastigotes; ^ehuman-derived endothelial cell line (EA.hy926); ^fCL Brener strain T. cruzi trypomastigotes; ^gVERO cells (ATCC CCL81); ^hDm28c strain T. cruzi epimastigotes. TSC: 5-nitrofurylthiosemicarbazone (Figures 8 and 9); CTZ: clotrimazole; phendione: 1,10-phenanthroline-5,6-dione; tmp: 3,4,7,8-tetramethyl-1,10-phenanthroline; mpo: pyridine-2-thiolate-1-oxide; dppf: 1,1’-bis(dipheny1phosphino) ferrocene; trop: tropolone; 8HQ: 8-hydroxyquinoline; 8HQNO₂: 5-nitro-8-quinolinol; 8HQClI: 5-chloro-7-iodo-8-quinolinol; bipy: 2,2’-bipyridine; 8HQII: 5,7-diiodo-8-quinolinol. SI: IC_W mammalian cell model/IC₅₀ parasite; IC₅₀ nifurtimox (7. cruzi): 24.7 μM (Dm28c trypomastigotes), 8.0 μM (Y strain epimastigotes), 20.1 μM (CL Brener strain trypomastigotes), 6.0 μM (Dm28c epimastigotes); IC₅₀ nifurtimox (7. brucei brucei): 6 μM (SI J774: 23).¹⁰⁷

Figure 9
Hit organometallic antitrypanosomal compounds obtained by Gambino and co-workers.⁹², ⁹³, ⁹⁴, ⁹⁵, ⁹⁶, ⁹⁷, ⁹⁸, ⁹⁹, ¹⁰⁰, ¹⁰¹, ¹⁰², ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶, ¹⁰⁷ Compounds are numbered as in Table 1.

While the various hit compounds presented in Table 1 cannot be strictly compared in terms of their activity against T. cruzi since they were evaluated at different stages of research by the Gambino group using different forms and strains of the parasite, practically all IC₅₀ values presented in the table fall within the submicromolar range, demonstrating a high antitrypanosomal activity of the organometallic compounds developed compared to the reference drug nifurtimox.

The first attempts by the group to develop organometallic antitrypanosomal compounds involved Ru-arene half-sandwich compounds including 5-nitrofuryl derived thiosemicarbazones as ligands and p-cymene or cyclopentadienyl (Cp) as arene cores. The thiosemicarbazone moiety has been identified as a privileged structure in medicinal chemistry and particularly in the development of antiparasitic compounds.⁷⁸, ⁸⁰, ¹⁰⁸, ¹⁰⁹ The thiosemicarbazones, which incorporate the 5-nitrofurane pharmacophore illustrated in Figure 10, were designed as analogues of the commercial antitrypanosomal drug nifurtimox. In the majority of cases, these compounds exhibited greater activities against T. cruzi compared to the reference drug. Their mechanism of antiparasitic action involves the bioreduction of the nitro moiety, subsequently leading to the generation of ROS.¹¹⁰

Figure 10
Bioactive 5-nitrofuryl containing thiosemicarbazones.

Complexes of the formula [Ru^IICp(PPh3)(TSC-H)] and [Ru^II₂(η⁶-p-cymene)₂(TSC-H)₂]X₂, with X = chloride and/or hexafluorophosphate as counterions, were obtained.⁹², ⁹³, ⁹⁴

The Ru-cyclopentadienyl compounds exhibited in vitro activity against the blood circulating trypomastigote form of T. cruzi and the infective form of T. brucei brucei, displaying IC₅₀ values in the micromolar range. A majority of these compounds demonstrated greater activity compared to the corresponding free TSC ligands and the antitrypanosomal drug nifurtimox. [Ru^IICp(PPh₃)(TSC3-H)] with the V-ethyl derivative TSC3 as ligand (Figure 10) was the most active one on both parasites showing an excellent selectivity towards T. cruzi and a good selectivity towards T. brucei (Table 1, Figure 9).⁹⁴

Among the Ru-p-cymene compounds, only [Ru^II₂( η⁶-p-cymene)₂(TSC4-H)₂]Cl₂ demonstrated significant activity against the relevant life cycle forms of both parasites, particularly showing high selectivity towards T. brucei. The remaining compounds displayed limited activity against T. cruzi and exhibited a similar level of effectiveness as the corresponding free ligands (TSC1-TSC3) against T. brucei. Furthermore, the results highlighted the influence of the counterion nature on the activity, with the more soluble chloride complexes being more active than the hexafluorophosphate ones.⁹³

In general, the complexation of the TSC ligands with the {RuCp(PPh₃)} moiety yielded superior results in terms of antiparasitic activity compared to the Ru-p-cymene counterpart. The biological findings indicate that both, [RuCp(PPh₃)(TSC-H)] and [Ru^II₂(η⁶-p-cymene)₂(TSC-H)₂]²+ complexes, generate deleterious free radicals through bioreduction within the parasite, resembling the free TSC. Moreover, these compounds display DNA interaction. Nevertheless, the observed biological activity does not seem to align straightforwardly with the magnitude of these effects, suggesting a more intricate “multiple-target” mechanism of action.⁹⁴

Later on, clotrimazole (CTZ) was selected as ligand for the development of the ruthenium cyclopentadienyl compound [RuCp(PPh₃)₂(CTZ)](CF₃SO₃) (Figure 9).⁹⁵ The formation of azole-metal complexes has been suggested as a strategy for creating agents targeting trypanosomatid parasites. Notably, complexes involving CTZ have exhibited promising outcomes. CTZ functions by inhibiting the sterol 14-α-demethylase enzyme, which plays a crucial role in converting lanosterol to zymosterol during the biosynthetic pathway leading to the parasite-specific sterol ergosterol.¹¹¹ The novel compound demonstrated significant cytotoxic activity against T. cruzi, exhibiting a sixfold increase compared to free CTZ. While CTZ alone lacks activity against T. brucei brucei (IC₅₀ > 25 μM), its complexation with the {RuCp} moiety resulted in a 40-fold higher activity than free CTZ (Table 1). The compound displayed only moderate selectivity toward both parasites, T. cruzi and T. brucei, in comparison to mammalian cells. Despite the anticipation of a dual antiparasitic mechanism arising from the presence of Ru^II and CTZ in a single molecule, the compound does not impact DNA but inhibits the sterol biosynthetic pathway in T. cruzi, specifically at the conversion of squalene to squalene oxide.⁹⁵

On the other hand, Moreno and co-workers⁹⁶ developed in collaboration with Gambino’s group five novel ruthenium(II)-p-cymene compounds with bidentate and monodentate polycyclic aromatic ligands. While the free ligands exhibited higher activity against T. brucei compared to the Ru^II compounds, the latter demonstrated reduced toxicity on mammalian cells. In all examined compounds, the complexation to the ruthenium-p-cymene core significantly decreased the cytotoxicity of the free ligands by a minimum of 30-fold. [RuCl(η⁶-p-cymene)(phendione)][PF₆], with phendione = 1,10-phenanthroline-5,6-dione, showed the highest activity (IC₅₀ of nM value) of the series on the infective form of T. brucei together with the highest selectivity towards the parasite (Figure 9, Table 1). According to the criteria defined by the Special Programme for Research and Training in Tropical Diseases (TDR),¹¹² this compound was considered as a hit drug for African trypanosomiasis. These ruthenium-p-cymene compounds, featuring polycyclic aromatic ligands, were observed to associate with DNA, and their interaction with this biomolecule was primarily believed to occur through the intercalation of the aromatic ligand.⁹⁶

Since the fac-tricarbonyl metal(I) moiety, fac- {M(CO)₃}⁺, had been scarcely explored for the development of antiparasitic drugs, Re tricarbonyl complexes with different bioactive ligands were also developed by the group. In a first attempt a series of fac-[Re^I(CO)₃Br(semicarbazone)] compounds was reported¹¹³ that showed only low in vitro activity on T. cruzi (IC₅₀ values 57-67 μM).

Later on, three fac-[Re^I(CO)₃Br(TSC)] compounds were obtained. The chosen TSC ligands comprised two derivatives characterized by varying chain length linking the thiosemicarbazone and nitrofuran moieties (TSC1 and TSC5), along with the more voluminous and lipophilic compound TSC4 (Figure 10). The compounds demonstrated a 4- to 17-fold enhancement in activity compared to the TSC ligands and proved to be 8-15 times more potent than nifurtimox. Furthermore, these compounds exhibited moderate to good selectivity indexes, falling within the range of 11-22. Although the most lipophilic TSC4 compound was the most active one, fac-[Re^I(CO)₃Br(TSC5)] showed a similarly low IC₅₀ value and the highest SI value of the series (Table 1).⁸¹, ⁹⁷ Through ¹H NMR (¹H nuclear magnetic resonance) and MS (mass spectroscopy) studies conducted over time, it was observed that fac-[Re(CO)₃Br(TSC)] species underwent conversion into dimers [Re₂(CO)₆(TSC-H)₂] in solution. Spin trapping ESR (electron spin resonance) investigations indicated that the studied compounds did not generate radical oxygen species in the parasite, unlike 5-nitrofuryl-derived thiosemicarbazones TSC. This difference is likely attributed to the unfavorable nitro reduction potential observed for the generated dimeric species [Re₂(CO)₆(TSC-H)₂]. Conversely, the compounds led to a reduction in the oxygen consumption rate of the parasites, possibly by inhibiting their mitochondrial respiration.⁹⁷

In a recent advancement, Gambino and co-workers⁹⁸ devised a series of six multifunctional Re^I tricarbonyl compounds. Each compound integrated two distinct bioactive ligands: a polypyridyl NN derivative and a monodentate azole (CTZ or ketoconazole, KTZ). The chosen NN ligands encompassed 2,2’-bipyridine (bpy), 4,4’-dimethyl 2,2’-bipyridine (dmb), 1,10-phenanthroline (phen), 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp), and 5-amino-1,10-phenanthroline (aminophen). The collection of five fac-[Re(CO)₃(NN)(CTZ)]PF₆ compounds displayed remarkable efficacy against T. cruzi trypomastigotes, with IC₅₀ values in the low μM range. Notably, they displayed heightened activity compared to the free ligands and nifurtimox, being their IC₅₀ values approximately ten times lower than that of the reference antitrypanosomal drug. Furthermore, these compounds exhibited a moderate to favorable selectivity towards the parasites when compared to the VERO mammalian cell model. Among the series, [Re(CO)₃(tmp)(CTZ)]PF₆ emerged as the most active and selective compound (Table 1, Figure 9). Despite exhibiting increased lipophilicity compared to the free bioactive ligands, no clear correlation between antitrypanosomal activity and lipophilicity was identified. Metallomics studies⁹⁹ were conducted on the compound using Raman confocal microscopy and MP-AES (microwave plasma atomic emission spectrometry). The results revealed a low overall uptake of rhenium by parasites (ca. 1.2%) and a notable accumulation preference within the soluble proteins fraction of the parasite (ca. 82.8%) in respect to insoluble, DNA and RNA (ribonucleic acid) fractions. Two potential molecular targets, DNA and the enzyme CYP51 (lanosterol 14-α-demethylase), underwent both experimental and theoretical investigations. The compound demonstrated an ability to interact with DNA while also influencing the membrane sterol biosynthesis of the parasite. This led to thable and groundbreaking example has been the development by the Brocard and Biot French group⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰ of the ferrocenyl derivative of the antimalarial drug chloroquine, known as ferroquine (Figure 7). The ferrocene moiety was incorporated into the lateral side-chain of the chloroquine skeleton. Chloroquine (Figure 7) was initially introduced as a main antimalarial drug in 1945, owing to its affordability, ease of use, and potent an

The success of ferrocenes in antitumoral and antimalarial drugs design lead to the interest of the group in searching for novel ferrocenyl derivatives as prospective agents against trypanosomatid parasites. In addition to the advantages of ferrocene in drug design previously described, ferrocene and its derivatives exhibit enhanced bioaccumulation compared to ionic forms of iron, being iron supply very important for parasites survival. Moreover, the induced generation of ROS by ferrocene derivatives, such as ferroquine, in a Fenton-like manner may hold therapeutic significance, given the heightened sensitivity of trypanosomatid parasites to radical species.⁶, ⁷⁰, ⁷⁷

Rather than the conventional approach of coupling the ferrocene scaffold to an organic skeleton, as seen in ferroquine or ferrocifen, our synthetic strategy involved incorporating the ferrocene fragment as a co-ligand within the platinum(II), palladium(II), or ruthenium(II) coordination sphere. The chosen co-ligand, 1,1’-bis(diphenylphosphino)ferrocene, abbreviated as dppf (Figure 11a), serves as a bidentate ligand by binding to the additional metal center through its two phosphorus donor atoms. This arrangement leaves the remaining coordination positions of the metal center available for coordination with the selected bioactive bidentate ligand.

Figure 11
(a) 1,1’-Bis(dipheny1phosphino) ferrocene, dppf; (b) structure of [M(L)(dppf)](PF₆) compounds, where M = Pt^II or Pd^II and L = mpo, trop, hino, TSC, 8HQs and (c) structure of [Ru^II(8HQs)(dppf)(NN)] (PF₆), where NN = 1,10-phenanthroline derivatives.

Twenty-four structurally related Pd^II or Pt^II ferrocenyl compounds [M(L)(dppf)](PF₆) (4 series with different families of ligands with the general structure depicted in Figure 11b) were synthesized and thoroughly characterized. Their impact was evaluated on both trypanosomes and mammalian cell models. Their effects on selected molecular targets were studied, and for the most promising pyridine-2-thiolato-1-oxide (mpo) compounds, omic studies were performed. Overall, the incorporation of the ferrocene moiety resulted in interesting effects on the biological profile of the compounds. The selected hit compounds of each series are depicted in Figure 9 and Table 1.

At a first stage [M(L)(dppf)](PF₆) compounds, where L represents the bioactive ligand pyridine-2-thiolato-1-oxide (mpo) (Figure 8e), were synthesized and characterized.¹⁰⁰ Earlier studies by Turrens et al.¹¹⁴ showed that mpo hinders the growth of T. cruzi, both in culture and within infected mammalian myoblasts, inhibiting the parasite-specific enzyme NADH (nicotinamide adenine dinucleotide) fumarate reductase (TcFR). The compound affects all stages of the parasite’s life cycle, without causing any harm to mammalian cells. TcFR catalyzes the conversion of fumarate to succinate. Because succinate plays a vital role as a respiratory substrate for T. cruzi, supporting essential energy production, the absence of this enzyme in mammalian cells provides an appealing target for the development of drugs aimed at combating T. cruzi.¹¹⁴

Both [M(mpo)(dppf)](PF₆) compounds exhibited IC₅₀ values in the nanomolar range against T. cruzi epimastigotes (Dm28c and CL Brener strains) while demonstrating low cytotoxicity on a mammalian cell model (VERO epithelial cells, ATCC CCL81), which led to excellent selectivity toward the parasite (Table 1). The complexes were approximately 10-20 times more potent than nifurtimox and two- to five-fold more active than mpo sodium salt. Notably, the compounds demonstrated 2-4 times greater susceptibility against epimastigotes of the CL Brener strain (type VI) compared to the type I Dm28c strain. This underscores the well-known fact that the genetic diversity of the parasite can result in varying susceptibility to drugs. Both complexes also affected the trypomastigote infection process as well as the intracellular amastigotes replication.¹⁰¹, ¹⁰²

While both metal compounds exhibited nanomolar IC₅₀ values against the epimastigote stage of the parasite and demonstrated an enhanced inhibitory effect on the activity of TcFR compared to the free mpo ligand, the IC50 values for enzyme inhibition were several times higher than those for T. cruzi. This suggested that TcFR may not be the sole molecular target of the compounds within the parasite.¹⁰⁰

To uncover the mechanism of action of both analogous prospective drugs, high-throughput omics approaches were employed on treated T. cruzi parasites.¹⁰¹, ¹⁰², ¹¹⁵ Inorganic chemists have conventionally sought to discover and analyze molecular targets of metal-based drugs through in vitro methodologies. This process primarily hinged on the mechanistic characteristics of organic ligands and the central metal. On the other hand, omics studies serve as crucial tools for comprehensively unraveling the entire mechanism of action of metal-based drugs. Through proteomics, the identification and quantification of upregulated and downregulated cellular proteins resulting from drug effects and molecular target interactions, coupled with metallomics for quantifying cell uptake and subcellular distribution, and transcriptomics for assessing changes in gene expression, the whole omics approach provides a profound understanding of cellular events following the administration of a metallodrug.¹¹⁶

Globally, this study marked the first omics contribution aimed at unraveling the comprehensive spectrum of effects involved in the mechanism of action of potential metal-based drugs for the treatment of Chagas disease. Metallomics investigations revealed a significant uptake of Pt and Pd by the parasites. Comparing equal doses, the Pt compound exhibited a greater uptake compared to its Pd analogue. The distribution pattern of metals across the four examined macromolecular fractions (DNA, RNA, soluble proteins, and insoluble proteins, including membrane lipids) remained consistent, showcasing a preferential affinity for DNA. Proteomics and transcriptomics studies unveiled a multimodal mechanism of action, identifying several significant candidates as potential targets within the parasite. The comprehensive dataset suggested that the antitrypanosomal mechanism of action for both compounds is likely multimodal. Intriguingly, notable biological distinctions were observed between the two structurally analogous compounds, underscoring the importance of the metal center’s nature in influencing their biological behavior. Notably, the transcriptomics study indicated that the treatment with both compounds resulted in the downregulation of most genes coding for enzymes involved in the ergosterol biosynthesis pathway, among effects on other important parasite pathways.¹¹⁵ The identification of this biosynthesis route as a target for both compounds was validated through the determination of sterol levels in treated parasites using HPLC (high-performance liquid chromatography). The inhibitory effect on enzymes of the route resulted in the accumulation of intermediate sterols, specifically lanosterol and squalene, along with a dose-dependent decrease in ergosterol. Two enzymes in the entire pathway, phosphomevalonate kinase (PMK) and lanosterol 14-α demethylase (CYP51), exhibited reduced transcript levels, and no protein was detected in treated parasites according to the earlier proteomic studies.¹¹⁷ The stads were selected based on their IC₅₀ (half-maximal inhibitory concentration) and selectivity index values (SI = IC₅₀ mammalian cells/IC₅₀ parasite) (Table 1). Their structures are depicted in Figure 9.

While the various hit compounds presented in Table 1 cannot be strictly compared in terms of their activity against T. cruzi since they were evaluated at different stages of research by the Gambino group using different forms and strains of the parasite, practically all IC50 values presented in the table fall within the submicromolar range, demonstrating a high antitrypanosomal activity of the organometallic compounds developed compared to the reference drug nifurtimox.

Building upon the encouraging outcomes achieved with these [M(mpo)(dppf)](PF₆) compounds, three additional series of ferrocenyl Pd and Pt compounds were developed. These new series of [M(L)(dppf)](PF₆) compounds incorporated TSC, tropolones, or 8-hydroxyquinoline derivatives as bioactive ligands (Figures 8, 10 and 12), instead of mpo.¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶

Figure 12
Structures of the selected 8-hydroxyquinoline derivatives (8HQs) and tropolones (tropolone, Htrop; hinokitiol, Hhino).

Tropolones and their derivatives were chosen as bioactive ligands due to being considered as lead-like natural products in medicinal chemistry. The tropolone moiety offers significant potential for derivatization, allowing for improvements in metal binding abilities. Compounds such as tropolone, hinokitiol, and their derivatives, along with the corresponding metal complexes, have exhibited diverse biological activities.¹¹⁸, ¹¹⁹, ¹²⁰

On the other hand, medicinal chemists have shown keen interest in the 8-hydroxyquinoline moiety, thanks to its noteworthy biological activities. It is widely regarded as a privileged structure in the realm of drug development.¹²¹, ¹²², ¹²³

[M(dppf)(L)](PF₆) compounds, with M = Pd^II or Pt^II and HL = tropolone (Htrop) or hinokitiol (Hhino), demonstrated IC₅₀ values ranging from 1.2 to 4.5 μM against the bloodstream form of T. brucei. There was a significant increase in activity, along with enhanced selectivity towards the parasite compared to the free ligands. Platinum complexes were more selective than palladium ones. Figure 9 and Table 1 illustrate the structure, IC50 value on T. brucei, and selectivity index (SI) value of the hit compound of the series, [Pt(trop)(dppf)](PF₆). Moreover, coordination of the tropolones to the (M-dppf) moiety also led to a slight increase of the activity against Leishmania infantum amastigotes. No effect on the thiolredox homeostasis of the parasites is produced by the complexes’ action. DNA could be a probable, but not main, target of these compounds.

Eight novel heterobimetallic [M(dppf)(TSC-H)](PF₆) compounds, featuring Pt^II or Pd^II, were synthesized. Figure 9 and Table 1 illustrate the structure, IC₅₀ values on T. cruzi and T. brucei, and SI values of the most active and selective compound in the series, [Pt(TSC3-H)(dppf)](PF₆). The majority of these compounds exhibited potent activity, with IC₅₀ values falling within the low micromolar or submicromolar range against both T. cruzi and T. brucei. Interestingly, the platinum compounds demonstrated higher activities when compared to their palladium counterparts. The antiparasitic activities of these compounds surpassed those of the free thiosemicarbazone ligands, exhibiting a 3- to 24-fold increase against T. cruzi and up to a remarkable 99-fold increase against T. brucei. The compounds exhibited activity up to 26 times higher against T. cruzi and up to 30 times against T. brucei than nifurtimox. Moreover, the incorporation of the organometallic dppf co-ligand seems to contribute to decreased toxicity on mammalian cells and enhanced selectivity towards both parasites when compared to the free thiosemicarbazone compounds. Both the Pd and Pt compounds were found to interact with DNA and to impact the redox metabolism of T. cruzi, suggesting that they retained the anti-T. cruzi mechanism of action observed for the free ligands described earlier. However, there was no observed correlation between oxygen uptake and the generation of free oxygen radical species in the parasite or the interaction with DNA and the anti-T. cruzi activity. [Pt(TSC3-H)(dppf)](PF₆) exhibited no in vivo toxicity in Zebrafish (Danio rerio) embryos, which are commonly employed as a toxicity model in drug development, throughout the tested concentration range of 1-100 μM. There were no apparent signs of toxicity even after 48 h of treatment.

Furthermore, the ten [M(8HQs-H)(dppf)](PF₆) compounds, encompassing five 8-hydroxyquinoline derivatives (8HQs) as bioactive bidentate co-ligands (Figure 12), demonstrated IC₅₀ values against bloodstream T. brucei form within the submicromolar or micromolar range (IC₅₀: Pt compounds 0.14-0.93 μM; Pd compounds 0.33-1.2 μM). Notably, these compounds exhibited strong selectivity towards the parasite (SI: Pt compounds 11-48; Pd compounds 4 -102) in comparison to murine macrophages (cell line J774) selected as model mammalian cells. Figure 9 and Table 1 illustrate the structure, IC₅₀ values on T. brucei, and SI values of the hit Pt and Pd compounds of the series, [Pt(8HQClI-H)(dppf)](PF₆) and [Pd(8HQNO₂-H)(dppf)](PF₆). In most cases, the coordination of the bioactive 8HQs to the {Pt-dppf) moiety resulted in a significant increase in activity (11-to 41-fold). While some Pd compounds surpassed the corresponding 8HQ ligands in activity, the majority of Pd compounds displayed lower activity than their Pt analogues. Interestingly, the Pd compounds proved to be 2- to 45-fold more potent than the drug nifurtimox, whereas platinum complexes exhibited a striking 16- to 107-fold increase in potency compared to this reference drug. The findings from the conducted studies indicate that the mechanism of action for these complexes against T. brucei may involve DNA interaction, with an additional contribution of oxidative stress specifically for the Pt compounds.

Having identified [Pt(8HQClI-H)(dppf)](PF₆) as the most promising compound from the 8HQs series (Table 1), an exploratory pre-clinical therapeutic efficacy study was conducted in an acute murine model for HAT. The study involved mice infected with a bioluminescent cell line of T. brucei, enabling non-invasive in vivo imaging (Figure 13). While preliminary, the in vivo investigation indicated that the tested compound did not exhibit acute toxicity to the animals. Furthermore, the results suggested that although the compound demonstrated antiproliferative activity, leading to an extension of animal survival, it did not possess a curative effect.

Figure 13
Scheme of the non-invasive in vivo study.

A comprehensive investigation was conducted on the whole family of twenty-two structurally related M-dppf-L compounds, featuring the diverse bioactive ligands L. The focus of the study was to delve into the quantitative structure-activity relationships (QSAR) and discern the key structural parameters influencing anti-T. brucei activity. Such analyses are infrequent in inorganic medicinal chemistry, primarily due to the requisite abundance of structurally analogous compounds. Various physicochemical characteristics, encompassing lipophilic, electronic, and steric/topological properties, were considered as independent variables. Among the descriptors, electronic properties and the nature of the metal ion emerged as the most pivotal factors in determining efficacy. The QSAR findings indicate that ligands bearing electron-withdrawing substituents, coupled with high lipophilicity and platinum as the central atom, contribute to complexes exhibiting heightened anti-T. brucei activity.⁷⁷, ¹⁰⁵ The latest rationally designed modification of these promising M-dppf-L compounds has focused on creating multifunctional Ru^II ferrocenyl compounds as potential agents against trypanosomatid parasites. Having Ru^II center a six coordination, these compounds were designed to incorporate the bidentate dppf and two bioactive bidentate ligands, 8-hydroxyquinoline derivatives (8HQs) and polypyridyl ligands (NNs), within a single molecule. The three [Ru(8HQs)(dppf)(NN)](PF₆) compounds exhibited in vitro activity against bloodstream T. brucei, with IC₅₀ values ranging from 140 to 310 nM. Additionally, they demonstrated activity against Leishmania infantum promastigotes, with IC₅₀ values ranging from 3.0 to 4.8 μM. Notably, these compounds displayed favorable selectivity towards T. brucei compared to J774 murine macrophages, with SI ranging from 15 to 38. Figure 9 and Table 1 illustrate the structure, IC₅₀ value on etramethyl-1,10-phenanthroline; mpo: pyridine-2-thiolate-1-oxide; dppf: 1,1’-bis(dipheny1phosphino) ferrocene; trop: tropolone; 8HQ: 8-hydroxyquinoline; 8HQNO₂: 5-nitro-8-quinolinol; 8HQClI: 5-chloro-7-iodo-8-quinolinol; bipy: 2,2’-bipyridine; 8HQII: 5,7-diiodo-8-quinolinol. SI: IC_W mammalian cell model/IC₅₀ parasite; IC₅₀ nifurtimox (7. cruzi): 24.7 μM (Dm28c trypomastigotes), 8.0 μM (Y strain epimastigotes), 20.1 μM (CL Brener strain trypomastigotes), 6.0 μM (Dm28c epimastigotes); IC₅₀ nifurtimox (7. brucei brucei): 6 μM (SI J774: 23).¹⁰⁷

In summary, the approach by Gambino group for designing new ferrocene derivatives by including the ferrocene scaffold as the organometallic co-ligand 1,1’-bis(diphenylphosphino)ferrocene (dppf) resulted in the development of highly active and selective anti-T. cruzi and/or T. brucei compounds, in the form of Pd-Fe, Pt-Fe and Ru-Fe heterobimetallic compounds. This family of organometallics deserves further study as a source of prospective antitrypanosomal drugs.

2.4. Organometallic agents against parasitic diseases by helminths

In the last decade, there has been a growing interest in the design and development of organometallics as prospective drugs against parasitic diseases by helminths.⁶⁰, ¹²⁴ Helminths are parasitic worms that can infect humans and animals. Main worm-induced NTDs encompass soil-transmitted helminthiases, schistosomiasis, lymphatic filariasis, and onchocerciasis. These NTDs account for 45% of the global NTDs burden.¹²⁵

Schistosomiasis, a parasitic disease caused by Schistosoma worms, manifests as both acute and chronic conditions. Its prevalence is notable in tropical and subtropical regions of Africa, Asia, and Latin America, particularly affecting impoverished communities lacking access to safe drinking water, proper sanitation, and adequate hygiene. The transmission of schistosomiasis is linked to the contamination of freshwater sources by infected individuals who urinate and defecate in open water bodies. To combat schistosomiasis, the WHO employs a strategy focused on reducing the disease burden through periodic, targeted large-scale treatment with praziquantel, administered as preventive chemotherapy. Praziquantel, while recommended for its effectiveness, safety, and cost-efficiency, has limitations due to its minimal impact on eggs and immature worms and rather low metabolic stability in vivo. Given that praziquantel is currently the sole treatment for schistosomiasis, and that there are occasional reports of treatment failure and the risk of resistance development, there is an urgent need to explore and develop alternative drugs.¹²⁴, ¹²⁵, ¹²⁶, ¹²⁷, ¹²⁸

On the other hand, soil-transmitted helminth infections rank among the most widespread infections globally, impacting approximately 1.5 billion individuals, which accounts for 24% of the world’s population. These infections disproportionately affect the most impoverished and underserved communities, where access to clean water, sanitation, and hygiene is lacking, particularly in tropical and subtropical regions. Sub-Saharan Africa, China, South America, and Asia report the highest prevalence of these infections. The transmission of these helminths occurs through eggs present in the feces of infected individuals, contaminating the soil in areas marked by inadequate sanitation.¹²⁵, ¹²⁹

Lymphatic filariasis, also known as elephantiasis, stands as a painful and severely disfiguring NTD. It stems from an infection with nematodes (roundworms) transmitted through mosquito bites. The larvae find their way onto the skin and enter the body. Subsequently, these larvae migrate to the lymphatic vessels, maturing into adult worms and perpetuating a cycle of transmission. This disease affects more than 120 million individuals across 72 countries in the tropical and sub-tropical regions of Asia, Africa, the Western Pacific, and certain areas of the Caribbean and South America.¹³⁰

Among the efforts to develop organometallic drugs for treating diseases by parasitic helminths, like schistosomiasis, lymphatic filariasis and soil-transmitted helminthiases, Gasser and co-workers⁶⁰, ¹²⁴, ¹³¹ have made notable strides in this field. Following a methodology akin to the one detailed in previous sections for developing the antitumoral drug ferrocifen and the antimalarial drug ferroquine, an organometallic moiety was incorporated into an anthelmintic organic drug. Figure 14 displays the chosen drugs, including praziquantel, monepantel, oxamniquine and albendazole.

Figure 14
Antihelminthic drugs selected by Gasser and co-workers.⁶⁰, ¹²⁴, ¹³¹

Praziquantel, monepantel, oxamniquine and albendazole underwent derivatization and assessment as antischistosomal agents by the Keiser and Gasser group. To narrow down the scope, this review showcases the research conducted by the Gasser and co-workers¹³² on the use of praziquantel in this field. Within the 18 praziquantel ferrocenyl derivatives synthesized, only four compounds, devoid of the cyclohexane ring and featuring the ferrocenyl moiety linked to praziquanamine through various connectors, retained some level of activity. The alternative approach of inclusion of a chromium tricarbonyl moiety at the aromatic ring of praziquantel successfully led to two chromium tricarbonyl-praziquantel racemate derivatives 14 and 15 with remarkable in vitro antischistosomal activity (Figure 15). Both Cr(CO)₃-praziquantel racemates 14 and 15 showed in vitro IC₅₀ values of 0.25 and 0.27 μM, respectively, on adult S. mαnsoni worms (IC₅₀ praziquantel 0.1 μM). Additionally, they showed high selectivity towards the parasite in respect to MRC-5 human fibroblasts as mammalian cell model.¹³³ Interestingly, to discern the activity difference between Æ-diastereomers and S-diastereomers, four diastereomers of these compounds were synthesized. Similar to praziquantel, both Æ-diastereomers exhibited significant in vitro activity against adult S. mαnsoni (IC₅₀ = 0.08-0.13 μM), whereas the S-enantiomers displayed no detectable activity.¹³⁴, ¹³⁵

Figure 15
Selected organometallic compounds reported by Gasser and co-workers:¹³³ chromium tricarbonyl-praziquantel racemate derivatives 14 and 15; fluconazole and derivatives 16 and 17.

In vivo studies conducted on mice infected with adult S. mαnsoni demonstrated lower efficacy for racemic mixtures of both complexes compared to racemic praziquantel.¹³⁴ To identify the biological targets of the most potent chromium compound 14 (depicted in Figure 15), researchers employed combined imaging by X-ray fluorescence (XRF) and infrared (IR) absorption spectromicroscopy. This approach revealed the organometallic compound’s localization within the schistosome. Distinctive IR CO stretchings and the chromium XRF feature indicated a notable accumulation of the compound in the worm’s tegument, the site where biological targets for praziquantel are thought to reside.¹³⁶

Related strategies were developed by Gasser and co-workers to derivatize the anthelmintic drugs monepantel,¹³⁷, ¹³⁸, ¹³⁹ oxamniquine,¹⁴⁰, ¹⁴¹ and albendazole.¹⁴² Further new antischistosomal drug candidates were also obtained by the organometallic derivatization of non-antifungal drugs like the antimalarial mefloquine.¹⁴³ The findings affirm the potential of developing organometallic derivatives of organic drugs as therapeutic agents against medically and veterinary significant parasites.

Gasser group have expanded its research by developing organometallic derivatives of the well-established antifungal drug fluconazole that showed promise as potential agents against parasitic helminths responsible for both soil-transmitted helminthiasis and lymphatic filariasis. The incorporation of organometallic moieties into the organic drug’s structure not only enhanced the antifungal activity of the original drug but also broadened its spectrum of action. Ten organometallic derivatives were obtained by replacement of one of the triazole rings of fluconazole by ferrocene or ruthenocene together with changes on the aliphatic linker. In vivo studies have demonstrated the compounds’ high effectiveness against pathogenic fungal infections, while in vitro experiments have revealed their potency against parasitic nematodes such as Brugia pahangi, causative agent of lymphatic filariasis, and Trichuris muris, a useful model for Trichuris trichiura (whipworm), one of the principal soil-transmitted helminths affecting humans. The ferrocenyl compound showing best performance of the series, compound 16 (Figure 15), displayed improved antifungal activity together with IC50 values in μM of 9 on Brugia pahangi and 23.9 on Trichuris muris.¹⁴⁴ It effectively reduced the reproductive output and fecundity of B. pahangi in vivo. These new compounds target specific molecular pathways, differing in their mechanism of action from fluconazole. Importantly, they exert their effects on biosynthetic pathways that are not present in the human host, enhancing their specificity and minimizing potential adverse effects.¹⁴⁵

In a subsequent approach, a similar strategy was employed, but with the substitution with the metallocenyl moieties ferrocene, ruthenocene, and cobaltocenium on one of the two identical triazoles in fluconazole. The incorporation of different metallocenes was intended to deepen the understanding of the impact of the metallocene moiety on the biological properties. Two synthetic methodologies were employed to produce fluconazole analogues, which depended on the type of linker, either 1,2,3-triazole or amide, connecting the organometallic group to the fluconazole core.¹⁴⁶

Although ruthenocene and ferrocene are isoelectronic and possess very similar geometry and steric demands, ruthenocene exhibits distinct redox properties compared to ferrocene.¹⁴⁷ The utilization of the isoelectronic cobaltocenium in existing drugs has been considerably less explored compared to the extensively studied ferrocene-containing bioactive compounds.¹⁴⁸

The hit compound 17 (Figure 15) proved effective in inducing worm death against both Brugia pahangi and Trichuris muris at concentrations of 50 and 100 μM, respectively. Toxicity assessment on the free-living nematode C. elegans, commonly utilized for testing the toxicity of potential drugs, indicated that this compound is non-toxic up to a dose of 100 μM, as it did not exhibit any noticeable impact on motility, viability, or development in this invertebrate animal. Additionally, this compound showed micromolar activity on T. cruzi and also some antifungal activity.

Overall, both studies underscore that the organometallic derivatization of known antifungal drugs can yield novel, easily synthesizable compounds with potent biological activity and broad spectrum. This type of organometallics should be further investigated to get novel compounds active against neglected diseases by parasitic helminths.

3. Conclusions

According to the findings highlighted in this review, organometallic compounds present a promising avenue for drug development that remains relatively untapped. Bioorganometallic chemistry holds significant potential for the creation of innovative drugs targeting prevalent neglected diseases caused by trypanosomatid parasites and parasitic worms, and malaria. This potential stems from the diverse bonding modes and structures available, as well as the adaptability this field offers in design. Generally, these compounds have demonstrated adequate stability in biological environments and suitable lipophilicity for in vivo applications. According to Lipinski’s rule, drugs typically have physicochemical and structural properties within certain ranges. Although metal compounds often do not follow the guidelines for drug-like properties of organic molecules, a balanced lipophilicity plays a significant role in determining pharmacokinetics properties of the compounds. Metal compounds with an appropriate level of lipophilicity are more likely to exhibit favorable ADME (absorption, distribution, metabolism, and excretion) profiles, leading to a suitable bioavailability.¹

The identification of the parasite targets affected is crucial to understand activity, unspecific cytotoxicity and selectivity towards the parasites and for the design of compounds with improved biological performance. Leveraging omics studies in parasites provides deeper insights into the potential antiparasitic actions of these compounds.

While this review highlights selected examples of established classes of organometallic compounds, there is ample opportunity for further research focused on rational design using these organometallic cores. Such endeavors would be of great interest to the fields of Medicinal Inorganic Chemistry and, particularly, Bioorganometallic Chemistry.

References

• ¹
  Anthony, E. J.; Bolitho, E. M.; Bridgewater, H. E.; Carter, O. W. L; Donnelly, J. M.; Imberti, C.; Lant, E. C.; Lermyte, F.; Needham, R. J.; Palau, M.; Sadler, P. J.; Shi, H.; Wang, F.-X.; Zhang, W.-Y.; Zhang, Z.; Chem. Sci. 2020, 11, 12888. [Crossref]
  » Crossref
• ²
  Kostenkova, K.; Scalese, G.; Gambino, D.; Crans, D. C.; Curr. Opin. Chem. Biol. 2022, 69, 102155. [Crossref]
  » Crossref
• ³
  Scalese, G.; Kostenkova, K.; Crans, D. C.; Gambino, D.; Curr. Opin. Chem. Biol. 2022, 67, 102127. [Crossref] and references therein.
  » Crossref
• ⁴
  Rosenberg, B.; Van Camp, L.; Krigas, T.; Nature 1965, 698. [Crossref]
  » Crossref
• ⁵
  Van Cleave, C.; Crans, D. C.; Inorganics2019, 7, 111. [Crossref]
  » Crossref
• ⁶
  Gasser, G.; Ott, I.; Metzler-Nolte, N.; J. Med. Chem. 2011, 54, 3. [Crossref]
  » Crossref
• ⁷
  Fish, R. H.; Jaouen, G.; Organometallics 2003, 22, 2166. [Crossref]
  » Crossref
• ⁸
  Jaouen, G.; Bioorganometallics; John Wiley & Sons: Weinheim, Germany, 2006.
• ⁹
  Hillard, E. A.; Jaouen, G.; Organometallics 2011, 30, 20. [Crossref]
  » Crossref
• ¹⁰
  Noffke, A. L.; Habtemariam, A.; Pizarro, A. M.; Sadler, P. J.; Chem. Commun. 2012, 48, 5219. [Crossref]
  » Crossref
• ¹¹
  Hartinger, C. G.; Dyson, P. J.; Chem. Soc. Rev. 2009, 38, 391. [Crossref]
  » Crossref
• ¹²
  Allardyce, C. S.; Dorcier, A.; Scolaro, C.; Dyson, P. J.; Appl. Organomet. Chem. 2005, 19, 1. [Crossref]
  » Crossref
• ¹³
  Dyson, P. J.; Sava, G.; Dalton Trans. 2006, 1929. [Crossref]
  » Crossref
• ¹⁴
  Chellan, P.; Sadler, P. J.; Chem. - Eur. J. 2020, 26, 8676. [Crossref]
  » Crossref
• ¹⁵
  Zhang, P.; Sadler, P. J.; J. Organomet. Chem. 2017, 839, 5. [Crossref]
  » Crossref
• ¹⁶
  van Rijt, S. H.; Sadler, P. J.; Drug Discovery Today 2009, 14, 1089. [Crossref]
  » Crossref
• ¹⁷
  Yan, Y. K.; Melchart, M.; Habtemariam, A.; Sadler, P. J.; Chem. Commun. 2005, 4764. [Crossref]
  » Crossref
• ¹⁸
  Braga, S. S.; Silva, A. M. S.; Organometallics 2013, 32, 5626. [Crossref]
  » Crossref
• ¹⁹
  Ong, Y. C.; Gasser, G.; Drug Discovery Today: Technol. 2020, 37, 117. [Crossref]
  » Crossref
• ²⁰
  Gasser, G.; Chimia 2015, 69, 442. [Crossref]
  » Crossref
• ²¹
  Patra, M.; Gasser, G.; ChemBioChem2012, 13, 1232. [Crossref]
  » Crossref
• ²²
  Gasser, G.; Metzler-Nolte, N.; Curr. Opin. Chem. Biol. 2012, 16, 84. [Crossref]
  » Crossref
• ²³
  Frei, A.; Elliott, A. G.; Kan, A.; Dinh, H.; Bräse, S.; Bruce, A. E.; Bruce, M. R.; Chen, F.; Humaidy, D.; Jung, N.; King, A. P.; Lye, P. G.; Maliszewska, H. K.; Mansour, A. M.; Matiadis, D.; Muñoz, M. P.; Pai, T.-Y.; Pokhrel, S.; Sadler, P. J.; Sagnou, M.; Taylor, M.; Wilson, J. J.; Woods, D.; Zuegg, J.; Meyer, W.; Cain, A. K.; Cooper, M. A.; Blaskovich, M. A. T.; JACS Au 2022, 2, 2277. [Crossref]
  » Crossref
• ²⁴
  Lin, Y.; Betts, H.; Keller, S.; Cariou, K.; Gasser, G.; Chem. Soc. Rev. 2021, 50, 10346. [Crossref]
  » Crossref
• ²⁵
  Oehninger, L.; Rubbiani, R.; Ott, I.; Dalton Trans. 2013, 42, 3269. [Crossref]
  » Crossref
• ²⁶
  Gil-Moles, M.; Türck, S.; Basu, U.; Pettenuzzo, A.; Bhattacharya, S.; Rajan, A.; Ma, X.; Bussing, R.; Wölker, J.; Burmeister, H.; Hoffmeister, H.; Schneeberg, P.; Prause, A.; Lippmann, P.; Kusi-Nimarko, J.; Hassell-Hart, S.; McGown, A.; Guest, D.; Lin, Y.; Notaro, A.; Vinck, R.; Karges, J.; Cariou, K.; Peng, K.; Qin, X.; Wang, X.; Skiba, J.; Szczupak, L·.; Kowalski, K.; Schatzschneider, U.; Hemmert, C.; Gornitzka, H.; Milaeva, E. R.; Nazarov, A. A.; Gasser, G.; Spencer, J.; Ronconi, L.; Kortz, U.; Cinatl, J.; Bojkova, D.; Ott, I.; Chem. - Eur. J. 2021, 27, 17928. [Crossref]
  » Crossref
• ²⁷
  Karges, J.; Giardini, M. A.; Blacque, O.; Woodworth, B.; Siqueira-Neto, J. L.; Cohen, S. M.; Chem. Sci. 2023, 14, 711. [Crossref]
  » Crossref
• ²⁸
  Köpf, H.; Köpf-Maier, P.; Angew. Chem. 1979, 91, 509. [Crossref]
  » Crossref
• ²⁹
  Guo, M.; Sun, H.; McArdle, H. J.; Gambling, L.; Sadler, P. J.; Biochemistry 2000, 39, 10023. [Crossref]
  » Crossref
• ³⁰
  Top, S.; Dauer, B.; Vaissermann, J.; Jaouen, G.; J. Organomet. Chem. 1997, 541, 355. [Crossref]
  » Crossref
• ³¹
  Jaouen, G.; Vessières, A.; Top, S.; Chem. Soc. Rev. 2015, 44, 8802. [Crossref]
  » Crossref
• ³²
  Top, S.; Tang, J.; Vessières, A.; Carrez, D.; Provot, C.; Jaouen, G.; Chem. Commun. 1996, 955. [Crossref]
  » Crossref
• ³³
  Wang, R.; Chen, H.; Yan, W.; Zheng, M.; Zhang, T.; Zhang, Y.; Eur. J. Med. Chem. 2020, 190, 112109. [Crossref]
  » Crossref
• ³⁴
  Idlas, P.; Lepeltier, E.; Jaouen, G.; Passirani, C.; Cancers2021, 13, 2291. [Crossref]
  » Crossref
• ³⁵
  Coverdale, J. P.; Laroiya-McCarron, T.; Romero-Canelón I.; Inorganics 2019, 7, 31. [Crossref]
  » Crossref
• ³⁶
  Rausch, M.; Dyson, P. J.; Nowak-Sliwinska, P.; Adv. Ther. 2019, 2, 1900042. [Crossref]
  » Crossref
• ³⁷
  Hanif, M.; Babak, M. V.; Hartinger, C. G.; Drug Discovery Today 2014, 19, 1640. [Crossref]
  » Crossref
• ³⁸
  Meier-Menches, S. M.; Gerner, C.; Berger, W.; Hartinger, C. G.; Keppler, B. K.; Chem. Soc. Rev. 2018, 47, 909. [Crossref]
  » Crossref
• ³⁹
  Hearn, J. M.; Romero-Canelón, I.; Qamar, B.; Liu, Z.; Hands-Portman, I. Sadler, P. J.; ACS Chem. Biol. 2013, 8, 1335. [Crossref]
  » Crossref
• ⁴⁰
  Liu, Z.; Sadler, P. J.; Acc. Chem. Res. 2014, 47, 1174. [Crossref]
  » Crossref
• ⁴¹
  Konkankit, C. C.; Marker, S. C.; Knopf, K. M.; Wilson, J. J.; Dalton Trans. 2018, 47, 9934. [Crossref]
  » Crossref
• ⁴²
  Leonidova, A.; Gasser, G.; ACS Chem. Biol. 2014, 9, 2180. [Crossref]
  » Crossref
• ⁴³
  Jürgens, S.; Herrmann, W. A.; Kühn, F. E.; J. Organomet. Chem. 2014, 751, 83. [Crossref]
  » Crossref
• ⁴⁴
  Bauer, E. B.; Haase, A. A.; Reich, R. M.; Crans, D. C.; Kühn, F. E.; Coord. Chem. Rev. 2019, 393, 79. [Crossref]
  » Crossref
• ⁴⁵
  Clède, S.; Policar, C.; Chem. - Eur. J. 2015, 21, 942. [Crossref]
  » Crossref
• ⁴⁶
  Policar, C.; Bouvet, J.; Bertrand, H. C.; Delsuc, N.; Curr. Opin. Chem. Biol. 2022, 67, 102109. [Crossref]
  » Crossref
• ⁴⁷
  Hostachy, S.; Policar, C.; Delsuc, N.; Coord. Chem. Rev. 2017, 351, 172. [Crossref]
  » Crossref
• ⁴⁸
  Cinellu, M. A.; Ott, I.; Casini, A. In Bioorganometallic Chemistry; Jaouen, G.; Salmain, M., eds.; Wiley-VCH: Weinheim, 2015, p. 117-140.
• ⁴⁹
  de Paiva, R. E. F.; Marçal Neto, A.; Santos, I. A.; Jardim, A. C. G.; Corbi, P. P.; Bergamini, F. R. G.; Dalton Trans. 2020, 49, 16004. [Crossref]
  » Crossref
• ⁵⁰
  Karges, J.; Cohen, S. M.; ChemBioChem 2021, 22, 2600. [Crossref]
  » Crossref
• ⁵¹
  Ioannou, K.; Vlasiou, M. C.; BioMetals 2022, 35, 639. [Crossref]
  » Crossref
• ⁵²
  Li, H.; Yuan, S. Wei, X.; Sun, H.; Chem. Commun. 2022, 58, 7466. [Crossref]
  » Crossref
• ⁵³
  Rothan, H. A.; Stone, S.; Natekar, J.; Kumari, P.; Arora, K.; Kumar, M.; Virology 2020, 547, 7. [Crossref]
  » Crossref
• ⁵⁴
  Cirri, D.; Marzo, T.; Tolbatov, I.; Marrone, A.; Saladini, F.; Vicenti, I.; Dragoni, F.; Boccuto, A.; Messori, L.; Biomolecules 2021, 11, 1858. [Crossref]
  » Crossref
• ⁵⁵
  Chuong, C.; DuChane, C. M.; Webb, E. M.; Rai, P.; Marano, J. M.; Bernier, C. M.; Merola, J. S.; Weger-Lucarelli, J.; Viruses 2021, 13, 980. [Crossref]
  » Crossref
• ⁵⁶
  Gil-Moles, M.; O’Beirne, C.; Esarev, I. V.; Lippmann, P.; Tacke, M.; Cinatl Jr., J.; Bojkova, D.; Ott, I.; RSC Med. Chem. 2023, 14, 1260. [Crossref]
  » Crossref
• ⁵⁷
  Gil-Moles, M.; Basu, U.; Bussing, R.; Hoffmeister, H.; Türck, S.; Varchmin, A.; Ott, I.; Chem. - Eur. J. 2020, 26, 15140. [Crossref]
  » Crossref
• ⁵⁸
  World Health Organization (WHO), Veglected Tropical Diseases, https://www.who.int/news-room/questions-and-answers/item/neglected-tropical-diseases, accessed in May 2024.
  » https://www.who.int/news-room/questions-and-answers/item/neglected-tropical-diseases
• ⁵⁹
  Drugs for Neglected Diseases initiative (DNDi), Veglected Tropical Diseases - A Global Health Emergency, https://dndi.org/diseases/neglected-tropical-diseases/, accessed in May 2024.
  » https://dndi.org/diseases/neglected-tropical-diseases/
• ⁶⁰
  Ong, Y. C.; Roy, S.; Andrews, P. C.; Gasser, G.; Chem. Rev. 2019, 119, 730. [Crossref]
  » Crossref
• ⁶¹
  Hotez, P. J.; Aksoy, S.; Brindley, P. J.; Kamhawi, S.; PLoS Neglected Trop. Dis. 2020, 14, e0008001. [Crossref]
  » Crossref
• ⁶²
  World Health Organization, Malaria, https://www.who.int/news-room/questions-and-answers/item/malaria, accessed in May 2024.
  » https://www.who.int/news-room/questions-and-answers/item/malaria
• ⁶³
  Medicines for Malaria Venture (MMV), Malaria Facts and Statistics, https://www.mmv.org/malaria/malaria-facts-statistics, accessed in June 2024.
  » https://www.mmv.org/malaria/malaria-facts-statistics
• ⁶⁴
  Peter, S.; Aderibigbe, B. A.; Molecules 2019, 24, 3604. [Crossref]
  » Crossref
• ⁶⁵
  Mangawa, S. K.; Singh, S.; Curr. Top. Med. Chem. 2023, 23, 1503. [Crossref]
  » Crossref
• ⁶⁶
  Wani, W. A.; Jameel, E.; Baig, U.; Mumtazuddin, S.; Hun, L. T.; Eur. J. Med. Chem. 2015, 101, 534. [Crossref]
  » Crossref
• ⁶⁷
  Biot, C.; Glorian, G.; Maciejewski, L. A.; Brocard, J. S.; Domarle, O.; Blampain, G.; Millet, P.; Georges, A. J.; Abessolo, H.; Dive, D.; Lebibi, J.; J. Med. Chem. 1997, 40, 3715. [Crossref]
  » Crossref
• ⁶⁸
  Dubar, F.; Khalife, J.; Brocard, J.; Dive, D.; Biot, C.; Molecules 2008, 13, 2900. [Crossref]
  » Crossref
• ⁶⁹
  Pierrot, C.; Lafitte, S.; Dive, D.; Fraisse, L.; Brocard, J.; Khalife, J.; Int. J. Parasitol. 2005, 35, 1601. [Crossref]
  » Crossref
• ⁷⁰
  Biot, C.; Curr. Med. Chem.: Anti-Infect. Agents 2004, 3, 135. [Crossref]
  » Crossref
• ⁷¹
  Medicines for Malaria Venture (MMV), Chloroquine, https://www.mmv.org/malaria-medicines/history-antimalarials-drugs#:~:text=Chloroquine, accessed in May 2024.
  » https://www.mmv.org/malaria-medicines/history-antimalarials-drugs#:~:text=Chloroquine
• ⁷²
  NIH National Library of Medicine, Ferroquine, https://www.clinicaltrials.gov/search?term=ferroquine, accessed in May 2024.
  » https://www.clinicaltrials.gov/search?term=ferroquine
• ⁷³
  Abd-Rahman, A. N.; Zaloumis, S.; McCarthy, J. S.; Simpson, J. A.; Commons, R. J.; Antimicrob. Agents Chemother. 2022, 66, e01659-21. [Crossref]
  » Crossref
• ⁷⁴
  Medicines for Malaria Venture (MMV), ZY19489+ Ferroquine, https://www.mmv.org/mmv-pipeline-antimalarial-drugs/zy19489-ferroquine, accessed in May 2024.
  » https://www.mmv.org/mmv-pipeline-antimalarial-drugs/zy19489-ferroquine
• ⁷⁵
  Dubar, F.; Egan, T. J.; Pradines, B.; Kuter, D.; Ncokazi, K. K.; Forge, D.; Paul, J.-F.; Pierrot, C.; Kalamou, H.; Khalife, J.; Buisine, E.; Rogier, C.; Vezin, H.; Forfar, I.; Slomianny, C.; Trivelli, X.; Kapishnikov, S.; Leiserowitz, L.; Dive, D.; Biot, C.; ACS Chem. Biol. 2011, 6, 275. [Crossref]
  » Crossref
• ⁷⁶
  Biot, C.; Taramelli, D.; Forfar-Bares, I.; Maciejewski, L. A.; Boyce, M.; Nowogrocki, G.; Brocard, J. S.; Basilico, N.; Olliaro, P.; Egan, T. J.; Mol. Pharm. 2005, 2, 185. [Crossref]
  » Crossref
• ⁷⁷
  Gambino, D.; Otero, L.; Front. Chem. 2022, 9, 816266. [Crossref]
  » Crossref
• ⁷⁸
  Navarro, M.; Gabbiani, C.; Messori, L.; Gambino, D.; Drug Discovery Today 2010, 15, 1070. [Crossref]
  » Crossref
• ⁷⁹
  Gambino, D.; Coord. Chem. Rev. 2011, 255, 2193. [Crossref]
  » Crossref
• ⁸⁰
  Gambino, D.; Otero, L.; Inorg. Chim. Acta 2012, 393, 103. [Crossref]
  » Crossref
• ⁸¹
  Gambino, D.; Otero, L.; Inorg. Chim. Acta 2018, 472, 58. [Crossref]
  » Crossref
• ⁸²
  Gambino, D.; Otero, L. In Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic, vol. 19; Carver, P. L., ed.; De Gruyter: Berlin, Boston, 2019, p. 331. [Crossref]
  » Crossref
• ⁸³
  Gambino, D.; Otero, L. In Targeted Metallo-Drugs, Design, Development, and Modes of Action, vol. 24, 1^st ed.; Farkas, E.; Marmion, C. J., eds.; CRC Press: Boca Raton, 2023, ch. 7. [Crossref]
  » Crossref
• ⁸⁴
  Ribeiro, I.; Sevcsik, A.-M.; Alves, F.; Diap, G.; Don, R.; Harhay, M. O.; Chang, S.; Pecoul, B.; PLoS Neglected Trop. Dis. 2009, 3, e484. [Crossref]
  » Crossref
• ⁸⁵
  De Rycker, M.; Baragaña, B.; Duce, S. L.; Gilbert, I. H.; Nature 2018, 559, 498. [Crossref]
  » Crossref
• ⁸⁶
  Santos, S. S.; de Araújo, R. V.; Giarolla, J.; El Seoud, O.; Ferreira, E. I.; Int. J. Antimicrob. Agents 2020, 55, 105906. [Crossref]
  » Crossref
• ⁸⁷
  Kourbeli, V.; Chontzopoulou, E.; Moschovou, K.; Pavlos, D.; Mavromoustakos, T.; Papanastasiou, I. P.; Molecules 2021, 26, 4629. [Crossref]
  » Crossref
• ⁸⁸
  Aslett, M.; Aurrecoechea, C.; Berriman, M.; Brestelli, J.; Brunk, B. P.; Carrington, M.; Depledge, D. P.; Fischer, S.; Gajria, B.; Gao, X.; Gardner, M. J.; Gingle, A.; Grant, G.; Harb, O. S.; Heiges, M.; Hertz-Fowler, C.; Houston, R.; Innamorato, F.; Iodice, J.; Kissinger, J. C.; Kraemer, E.; Li, W.; Logan, F. J.; Miller, J. A.; Mitra, S.; Myler, P. J.; Nayak, V.; Pennington, C.; Phan, I.; Pinney, D. F.; Ramasamy, G.; Rogers, M. B.; Roos, D. S.; Ross, C.; Sivam, D.; Smith, D. F.; Srinivasamoorthy, G.; Stoeckert Jr., C. J.; Subramanian, S.; Thibodeau, R.; Tivey, A.; Treatman, C.; Velarde, G.; Wang, H.; Nucleic Acids Res. 2010, 38, D457. [Crossref]
  » Crossref
• ⁸⁹
  El-Sayed, N. M.; Myler, P. J.; Blandin, G.; Berriman, M.; Crabtree, J.; Aggarwal, G.; Caler, E.; Renauld, H.; Worthey, E. A.; Hertz-Fowler, C.; Ghedin, E.; Peacock, C.; Bartholomeu, D. C.; Haas, B. J.; Tran, A.-N.; Wortman, J. R.; Alsmark, U. C. M.; Angiuoli, S.; Anupama, A.; Badger, J.; Bringaud, F.; Cadag, E.; Carlton, J. M.; Cerqueira, G. C.; Creasy, T.; Delcher, A. L.; Djikeng, A.; Embley, T. M.; Hauser, C.; Ivens, A. C.; Kummerfeld, S. K.; Pereira-Leal, J. B.; Nilsson, D.; Peterson, J.; Salzberg, S. L.; Shallom, J.; Silva, J. C.; Sundaram, J.; Westenberger, S.; White, O.; Melville, S. E.; Donelson, J. E.; Andersson, B.; Stuart, K. D.; Hall, N.; Science 2005, 309, 404. [Crossref]
  » Crossref
• ⁹⁰
  Ilari, A.; Genovese, I.; Fiorillo, F.; Battista, T.; De Ionna, I.; Fiorillo, A.; Colotti, G.; Mol. Pharmaceutics 2018, 15, 3069. [Crossref]
  » Crossref
• ⁹¹
  Stuart, K.; Brun, R.; Croft, S.; Fairlamb, A.; Gürtler, R. E.; McKerrow, J.; Reed, S.; Tarleton, R.; J. Clin. Invest. 2008, 118, 1301. [Crossref]
  » Crossref
• ⁹²
  Demoro, B.; Sarniguet, C.; Sánchez-Delgado, R.; Rossi, M.; Liebowitz, D.; Caruso, F.; Olea-Azar, C.; Moreno, V.; Medeiros, A.; Comini, M. A.; Otero, L.; Gambino, D.; Dalton Trans. 2012, 41, 1534. [Crossref]
  » Crossref
• ⁹³
  Demoro, B.; Rossi, M.; Caruso, F.; Liebowitz, D.; Olea-Azar, C.; Kemmerling, U.; Maya, J. D.; Guiset, H.; Moreno, V.; Pizzo, C.; Mahler, G.; Otero, L.; Gambino, D.; Biol. TraceElem. Res. 2013, 153, 371. [Crossref]
  » Crossref
• ⁹⁴
  Fernández, M.; Rodríguez Arce, E.; Sarniguet, C.; Morais, T. S.; Tomaz, A. I.; Olea Azar, C.; Figueroa, R.; Maya, J. D.; Medeiros, A.; Comini, M.; Garcia, M. H.; Otero, L.; Gambino, D.; J. Inorg. Biochem. 2015, 153, 306. [Crossref]
  » Crossref
• ⁹⁵
  Rodríguez 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.; Garcia, M. H.; Otero, L.; Gambino, D.; J. Coord. Chem. 2015, 68, 2923. [Crossref]
  » Crossref
• ⁹⁶
  Miserachs, H. G.; Cipriani, M.; Grau, J.; Vilaseca, M.; Lorenzo, J.; Medeiros, A.; Comini, M. A.; Gambino, D.; Otero, L.; Moreno, V.; J. Inorg. Biochem. 2015, 150, 38. [Crossref]
  » Crossref
• ⁹⁷
  Rodríguez Arce, E.; Machado, I.; Rodríguez, B.; Lapier, M.; Zúñiga, M. C.; Maya, J. D.; Olea Azar, C.; Otero, L.; Gambino, D.; J. Inorg. Biochem. 2017, 170, 125. [Crossref]
  » Crossref
• ⁹⁸
  Soba, M.; Scalese, G.; Casuriaga, F.; Perez, N.; Veiga, N.; Echeverría, G. A.; Piro, O. E.; Faccio, R.; Pérez-Díaz, L.; Gasser, G.; Machado, I.; Gambino, D.; Dalton Trans. 2023, 52, 1623. [Crossref]
  » Crossref
• ⁹⁹
  Soba, M.; Scalese, G.; Pérez-Díaz, L.; Gambino, D.; Machado, I.; Talanta 2022, 244, 123413. [Crossref]
  » Crossref
• ¹⁰⁰
  Rodríguez Arce, E.; Florencia Mosquillo, M.; Pérez-Díaz, L.; Echeverría, G. A.; Piro, O. E.; Merlino, A.; Coitiño, E. L.; Maríngolo Ribeiro, C.; Leite, C. Q. F.; Pavan, F. R.; Otero, L.; Gambino, D.; Dalton Trans. 2015, 44, 14453. [Crossref]
  » Crossref
• ¹⁰¹
  Florencia Mosquillo, M.; Bilbao, L.; Hernández, F.; Machado, I.; Gambino, D.; Garat, B.; Pérez-Díaz, L.; Biometals 2018, 31, 961. [Crossref]
  » Crossref
• ¹⁰²
  Florencia Mosquillo, M.; Bilbao, L.; Hernández, F.; Tissot, F.; Gambino, D.; Garat, B.; Pérez-Díaz, L.; Chem. Biol. Drug Des. 2018, 92, 1657. [Crossref]
  » Crossref
• ¹⁰³
  Rodríguez Arce, E.; Putzu, E.; Lapier, M.; Maya, J. D.; Olea Azar, C.; Echeverría, G. A.; Piro, O. E.; Medeiros, A.; Sardi, F.; Comini, M.; Risi, G.; Salinas, G.; Correia, I.; Pessoa, J. C.; Otero, L.; Gambino, D.; Dalton Trans. 2019, 48, 7644. [Crossref]
  » Crossref
• ¹⁰⁴
  Rivas, F.; Medeiros, A.; Rodríguez Arce, E.; Comini, M.; Ribeiro, C. M.; Pavan, F. R.; Gambino, D.; J. Inorg. Biochem. 2018, 187, 73. [Crossref]
  » Crossref
• ¹⁰⁵
  Rivas, F.; Medeiros, A.; Quiroga, C.; Benítez, D.; Comini, M.; Rodríguez-Arce, E.; Machado, I.; Cerecetto, H.; Gambino, D.; Dalton Trans. 2021, 50, 1651. [Crossref]
  » Crossref
• ¹⁰⁶
  Rivas, F.; Medeiros, A.; Comini, M.; Suescun, L.; Rodríguez Arce, E.; Martins, M.; Pinheiro, T.; Marques, F.; Gambino, D.; J. Inorg. Biochem. 2019, 199, 110779. [Crossref]
  » Crossref
• ¹⁰⁷
  Rivas, F.; Del Mármol, C.; Scalese, G.; Pérez-Díaz, L.; Machado, I.; Blacque, O.; Medeiros, A.; Comini, M.; Gambino, D.; J. Inorg. Biochem. 2022, 237, 112016. [Crossref]
  » Crossref
• ¹⁰⁸
  Beraldo, H.; Gambino, D.; Mini-Rev. Med. Chem. 2004, 4, 31. [Crossref]
  » Crossref
• ¹⁰⁹
  Kumar, A.; Mishra, R.; Mazumder, A.; Mazumder, R.; Kumar, A.; Asian J. Chem. 2021, 33, 1957. [Crossref]
  » Crossref
• ¹¹⁰
  Aguirre, G.; Boiani, L.; Cerecetto, H.; González, M.; Denicola, A.; Otero, L.; Gambino, D.; Rigol, C.; Olea-Azar, C.; Faundez, M.; Bioorg. Med. Chem. 2004, 12, 4885. [Crossref]
  » Crossref
• ¹¹¹
  Scalese, G.; Florencia Mosquillo, M.; Pérez-Díaz, L.; Gambino, D.; Coord. Chem. Rev. 2024, 503, 215608. [Crossref]
  » Crossref
• ¹¹²
  Don, R.; Ioset, J. R. S.; Parasitology 2014, 14, 140. [Crossref]
  » Crossref
• ¹¹³
  Machado, I.; Fernández, S.; Becco, L.; Garat, B.; Gancheff, J. S.; Rey, A.; Gambino, D.; J. Coord. Chem. 2014, 67, 1835. [Crossref]
  » Crossref
• ¹¹⁴
  Turrens, J. F.; Newton, C. L.; Zhong, L.; Rafael Hernandez, F.; Whitfield, J.; Docampo, R.; FEMSMicrobiol. Lett. 1999, 175, 217. [Crossref]
  » Crossref
• ¹¹⁵
  Florencia Mosquillo, M.; Smircich, P.; Ciganda, M.; Lima, A.; Gambino, D.; Garat, B.; Pérez-Díaz, L.; Metallomics 2020, 12, 813. [Crossref]
  » Crossref
• ¹¹⁶
  Wang, H.; Zhou, Y.; Xu, X.; Li, H.; Sun, H.; Curr. Opin. Chem. Biol. 2020, 55, 171. [Crossref]
  » Crossref
• ¹¹⁷
  Florencia Mosquillo, M.; Scalese, G.; Moreira, R.; Denis, P. A.; Machado, I.; Paulino, M.; Gambino, D.; Pérez-Díaz, L.; ChemBioChem 2023, 24, e202300406. [Crossref]
  » Crossref
• ¹¹⁸
  Ononye, S. N.; VanHeyst, M. D.; Oblak, E. Z.; Zhou, W.; Ammar, M.; Anderson, A. C.; Wright, D. L.; ACS Med. Chem. Lett. 2013, 4, 757. [Crossref]
  » Crossref
• ¹¹⁹
  Saniewski, M.; Horbowicz, M.; Kanlayanarat, S.; J. Hortic. Res. 2014, 22, 5. [Crossref]
  » Crossref
• ¹²⁰
  El Hachlafi, N.; Lakhdar, F.; Khouchlaa, A.; Bakrim, S.; El Omari, N.; Balahbib, A.; Shariati, M. A.; Zengin, G.; Fikri-Benbrahim, K.; Orlando, G.; Ferrante, C.; Meninghi, L.; Bouyahya, A.; Processes 2021, 9, 1680. [Crossref]
  » Crossref
• ¹²¹
  Oliveri, V.; Vecchio, G.; Eur. J. Med. Chem. 2016, 120, 252. [Crossref]
  » Crossref
• ¹²²
  Song, Y.; Xu, H.; Chen, W.; Zhan, P.; Liu, X.; Med. Chem. Commun. 2015, 6, 61. [Crossref]
  » Crossref
• ¹²³
  Gupta, R.; Luxami, V.; Paul, K.; Bioorg. Chem. 2021, 108, 104633. [Crossref]
  » Crossref
• ¹²⁴
  Hess, J.; Keiser, J.; Gasser, G.; Future Med. Chem. 2015, 7, 821. [Crossref]
  » Crossref
• ¹²⁵
  Specht, S.; Keiser, J.; Int. J. Parasitol. 2023, 53, 411. [Crossref]
  » Crossref
• ¹²⁶
  World Health Organization (WHO), Schistosomiasis, https://www.who.int/news-room/fact-sheets/detail/schistosomiasis, accessed in June 2024.
  » https://www.who.int/news-room/fact-sheets/detail/schistosomiasis
• ¹²⁷
  Hotez, P. J.; Brindley, P. J.; Bethony, J. M.; King, C. H.; Pearce, E. J.; Jacobson, J.; J. Clin. Invest. 2008, 118, 1311. [Crossref]
  » Crossref
• ¹²⁸
  Greenberg, R. M.; Parasitology 2013, 140, 1534. [Crossref]
  » Crossref
• ¹²⁹
  World Health Organization (WHO), Soil-Transmitted Helminth Infections, https://www.who.int/news-room/fact-sheets/detail/soil-transmitted-helminth-infections, accessed in May 2024.
  » https://www.who.int/news-room/fact-sheets/detail/soil-transmitted-helminth-infections
• ¹³⁰
  World Health Organization (WHO), Lymphatic Filariasis (Elephantiasis), https://www.who.int/health-topics/lymphatic-filariasis, accessed in May 2024.
  » https://www.who.int/health-topics/lymphatic-filariasis
• ¹³¹
  Patra, M.; Gasser, G.; Nat. Rev. Chem. 2017, 1, 0066. [Crossref]
  » Crossref
• ¹³²
  Patra, M.; Ingram, K.; Pierroz, V.; Ferrari, S.; Spingler, B.; Keiser, J.; Gasser, G.; J. Med. Chem. 2012, 55, 8790. [Crossref]
  » Crossref
• ¹³³
  Patra, M.; Ingram, K.; Pierroz, V.; Ferrari, S.; Spingler, B.; Gasser, R. B.; Keiser, J.; Gasser, G.; Chem. - Eur. J. 2013, 19, 2232. [Crossref]
  » Crossref
• ¹³⁴
  Patra, M.; Ingram, K.; Leonidova, A.; Pierroz, V.; Ferrari, S.; Robertson, M. N.; Todd, M. H.; Keiser, J.; Gasser, G.; J. Med. Chem. 2013, 56, 9192. [Crossref]
  » Crossref
• ¹³⁵
  Meister, I.; Ingram-Sieber, K.; Cowan, N.; Todd, M.; Robertson, M. N.; Meli, C.; Patra, M.; Gasser, G.; Keiser, J.; Antimicrob. Agents Chemother. 2014, 58, 5466. [Crossref]
  » Crossref
• ¹³⁶
  Clède, S.; Cowan, N.; Lambert, F.; Bertrand, H. C.; Rubbiani, R.; Patra, M.; Hess, J.; Sandt, C.; Trcera, N.; Gasser, G.; Keiser, J.; Policar, C.; ChemBioChem 2016, 17, 1004. [Crossref]
  » Crossref
• ¹³⁷
  Hess, J.; Patra, M.; Jabbar, A.; Pierroz, V.; Konatschnig, S.; Spingler, B.; Ferrari, S.; Gasser, R. B.; Gasser, G.; Dalton Trans. 2016, 45, 17662. [Crossref]
  » Crossref
• ¹³⁸
  Hess, J.; Patra, M.; Pierroz, V.; Spingler, B.; Jabbar, A.; Ferrari, S.; Gasser, R. B.; Gasser, G.; Organometallics 2016, 35, 3369. [Crossref]
  » Crossref
• ¹³⁹
  Hess, J.; Patra, M.; Rangasamy, L.; Konatschnig, S.; Blacque, O.; Jabbar, A.; Mac, P.; Jorgensen, E. M.; Gasser, R. B.; Gasser, G.; Chem. - Eur. J. 2016, 22, 16602. [Crossref]
  » Crossref
• ¹⁴⁰
  Hess, J.; Panic, G.; Patra, M.; Mastrobuoni, L.; Spingler, B.; Roy, S.; Keiser, J.; Gasser, G.; ACS Infect. Dis. 2017, 3, 645. [Crossref]
  » Crossref
• ¹⁴¹
  Buchter, V.; Hess, J.; Gasser, G.; Keiser, J.; Parasites Vectors 2018, 11, 580. [Crossref]
  » Crossref
• ¹⁴²
  Lin, Y.; Ong, Y. C.; Keller, S.; Karges, J.; Bouchene, R.; Manoury, E.; Blacque, O.; Müller, J.; Anghel, N.; Hemphill, A.; Häberli, C.; Taki, A.; Gasser, R. B.; Cariou, K.; Keiser, J.; Gasser, G.; Dalton Trans. 2020, 49, 6616. [Crossref]
  » Crossref
• ¹⁴³
  d’Orchymont, F.; Hess, J.; Panic, G.; Jakubaszek, M.; Gemperle, L.; Keiser, J.; Gasser, G.; Med. Chem. Commun. 2018, 9, 1905. [Crossref]
  » Crossref
• ¹⁴⁴
  Klementowicz, J. E.; Travis, M. A.; Grencis, R. K.; Semin. Immunopathol. 2012, 54, 815. [Crossref]
  » Crossref
• ¹⁴⁵
  Lin, Y.; Jung, H.; Bulman, C. A.; Ng, J.; Vinck, R.; O’Beirne, C.; Zhong, S.; Moser, M. S.; Tricoche, N.; Peguero, R.; Li, R. W.; Urban Jr., J. F.; Le Pape, P.; Pagniez, F.; Moretto, M.; Weil, T.; Lustigman, S.; Cariou, K.; Mitreva, M.; Sakanari, J. A.; Gasser, G.; J. Med. Chem. 2023, 66, 15867. [Crossref]
  » Crossref
• ¹⁴⁶
  Lin, Y.; Scalese, G.; Bulman, C. A.; Vinck, R.; Blacque, O.; Paulino, M.; Ballesteros-Casallas, A.; Pérez Díaz, L.; Salinas, G.; Mitreva, M.; Weil, T.; Cariou, K.; Sakanari, J. A.; Gambino, D.; Gasser, G.; ACS Infect. Dis. 2024, 10, 938. [Crossref]
  » Crossref
• ¹⁴⁷
  Swarts, J. C.; Nafady, A.; Roudebush, J. H.; Trupia, S.; Geiger, W. E.; Inorg. Chem. 2009, 48, 2156. [Crossref]
  » Crossref
• ¹⁴⁸
  Chantson, J. T.; Falzacappa, M. V. V.; Crovella, S.; Metzler-Nolte, N.; J. Organomet. Chem. 2005, 690, 4564. [Crossref]
  » Crossref

Edited by

Editor handled this article: Carlos Maurício R. de Sant’Anna (guest)

In honor of Professor Eliezer J. L. Barreiro

Publication Dates

• Publication in this collection
  19 July 2024
• Date of issue
  2024

History

• Received
  08 Feb 2024
• Accepted
  17 June 2024