INTRODUCTION:The relentless surge of antimicrobial resistance (AMR) across bacterial, fungal, viral, and parasitic pathogens constitutes a catastrophic threat to global healthcare, rapidly rendering conventional organic anti-infectives obsolete and demanding the urgent development of innovative chemical scaffolds. AREAS COVERED:This expert opinion examines recent breakthroughs in bioorganometallic drug design. It evaluates the structural classification, multi-targeted mechanisms of action, non-canonical pathways, and preclinical efficacy of emerging organometallic compounds-specifically metallocenes, N-heterocyclic carbenes, half-sandwich arenes, and tricarbonyl complexes-combating drug-resistant infections. EXPERT OPINION:Organometallic platforms offer an unparalleled structural toolkit to overcome cross-resistance due to their modular geometries and ability to trigger simultaneous lethal mechanisms. To advance these candidates into human clinical trials and address lingering toxicity concerns, future research must prioritize optimizing the kinetic stability of metal-compounds networks to prevent premature in vivo speciation. Furthermore, integrating smart, pathogen-specific delivery vectors (such as peptide or antibody conjugates) will dramatically expand their therapeutic windows, facilitating the clinical translation of next-generation bioorganometallic anti-infectives.

Rhenium(I) tricarbonyl complexes bearing bioactive ligands represent a promising multifunctional scaffold for drug development. We developed a series of fac-[ReI(CO)3(N,N)(N-azole)]Cl complexes, where (N,N) are polypyridyl derivatives (1,10-phenanthroline and 2,2 '-bipyridine derivatives) and the N-azole ligands are clotrimazole (CTZ) or ketoconazole (KTZ). Exchange of the PF6- counterion for chloride improved aqueous solubility while preserving the fac-{Re(CO)3}+ core, enabling reliable evaluation in cell-based assays. The complexes were tested against clinically relevant stages of Trypanosoma cruzi, Trypanosoma brucei, and Leishmania infantum. Phenand tmp-containing complexes displayed the highest potency, reaching nanomolar EC50 values against T. brucei and outperforming the corresponding free ligands. Notably, [ReI(CO)3(tmp)(KTZ)]Cl was the only compound active against intracellular L. infantum, achieving parasite clearance at 5 mu M. Mechanistic studies showed that CYP51 overexpression in T. cruzi partially rescued parasite viability, supporting inhibition of ergosterol biosynthesis as one mode of action. Redox-reporter assays in bloodstream T. brucei revealed compound-induced oxidation of the intracellular thiol pool under high drug pressure, indicating disruption of thiol-dependent redox metabolism. Biological characterization was expanded to tumor and non-tumor mammalian cell lines (CT-26, U87 MG, and RPE-1). Tmp-azole complexes showed markedly higher cytotoxicity than the free ligands, with U-87 MG being the most sensitive line and exhibiting up to a 74-fold improvement over CTZ. Human liver microsome assays demonstrated ligand release and formation of metabolic derivatives, providing insights into in vivo stability. Overall, these findings support fac-Re(I) tricarbonyl complexes as versatile drug candidates and encourage further ligand-engineering efforts.

About 50 years after their development, the benzimidazole anthelmintic drugs still occupy a key role in the treatment of parasitic diseases. Like other anti-infective drugs, their extensive use has led to resistance development and now requires new solutions to treat these diseases. Organometallic derivatization of existing drugs has become a common strategy to design new drug candidates, which could benefit from enhanced activity against resistant or sensitive strains through the incorporation of an organometallic fragment. In this study, we describe the development of a new series of organometallic derivatives of benzimidazole anthelmintics. Ten derivatives, six of which were organometallic, were synthesized and characterized. In silico and in vitro studies were performed to determine their biological activity. Therefore, they were screened against a range of nematodes and other parasites. Biological activities were found for some of the derivatives against Strongyloides ratti, Ancylostoma ceylanicum, Trichuris muris, Schistosoma mansoni, Echinococcus multilocularis, or Leishmania infantum in similar ranges as the parent anthelmintics. Even if the activity of the benzimidazole scaffold was not systematically enhanced, this strategy is a good starting point for the development of new antiparasitic compounds and for further study of the mode of action of these drugs.

Polyoxovanadates (POVs) have been proposed as potential drugs against cancer and diabetes, as well as against viral and bacterial diseases. However, their potential application as bioactive compounds against trypanosomatid parasites remains unexplored. In this work, we evaluated for the first time the activity of decavanadate (V10) and monosubstituted V9M structures with M = Pt(IV), Mo(VI), and W(VI) on Trypanosoma cruzi. In some cases, activity increased by 1-2 orders of magnitude compared to monomeric vanadate (EC50 monomeric vanadate V1 > 1000 µM in epimastigotes and >100 µM in trypomastigotes, EC50 V10 in epimastigotes = 1.5 µM, EC50 V9Pt and V9Mo in trypomastigotes = 8.1 µM). Significant differences in activity were observed between the trypomastigote and epimastigote forms of the parasite. Cytotoxicity, evaluated in VERO cells, remained within the same order of magnitude for both decavanadate-type structures and monomeric vanadate. 51V NMR measurements performed in culture media showed that substitution significantly affects cluster stability and speciation. Metal uptake studies did not show differences that could explain the observed biological activity, and transcriptomic assays identified no significant impact at the gene expression level. These results are consistent with the interpretation that the effects occur at the proteomic level.

Searching for more effective chemotherapeutic agents for the treatment of American Trypanosomiasis, a disease caused by the parasite Trypanosoma cruzi (T. cruzi), the development of gold(I) compounds represents a promising strategy. In this work, four new cationic gold(I) compounds, [Au(HL)₂]Cl, where HL = 5-nitrofuryl-containing thiosemicarbazones, were synthesized and characterized in the solid state and in DMSO solution. Their cationic and radical structures were experimentally and theoretically studied. The formation of intermolecular aurophilic interactions and the lipophilicity of the complexes were also analyzed. Three gold(I) compounds displayed micromolar IC₅₀ values (around 10 μM) against T. cruzi bloodstream trypomastigotes and showed moderate selectivity towards the parasites with respect to human cells of endothelial morphology. Two of these complexes were more active than their respective thiosemicarbazone ligands and exhibited antiparasitic activity comparable to that of Nifurtimox. Lipophilicity and the presence of aurophilic interactions appear to play a key role in their antitrypanosomal activity. The active gold(I) compounds induced cytosolic reactive oxygen species (ROS) generation, disrupted mitochondrial membrane potential, and promoted mitochondrial ROS production, suggesting they may act as crucial precursors to mitochondria-mediated apoptotic cell death. In addition, DNA competitive binding with ethidium bromide, evaluated by fluorescence measurements, demonstrated that the compounds interact with this biomolecule. Overall, these three active gold(I) complexes can be considered promising hits for the development of prospective agents against T. cruzi.

Diseases caused by trypanosomatid parasites are among the most pressing neglected illnesses. Chagas disease, caused by Trypanosoma cruzi, and visceral Leishmaniasis, caused by Leishmania infantum, have a severe health impact in developing countries. Searching for prospective metal-based drugs against these diseases, five multifunctional fac-[Mn(CO)3(CTZ)(NN)](PF6) compounds, including four new derivatives, were synthesized and thoroughly characterized, featuring NN polypyridyl derivatives and Clotrimazole (CTZ) as bioactive ligands. The biological behavior was compared with that previously reported for the Re analogues. Mn compounds showed EC50 values in the low micromolar range against the infective trypomastigote form of Trypanosoma cruzi and the promastigote form of Leishmania infantum and moderate selectivity indexes. While their potency against T. cruzi was comparable to the Re analogues, their selectivity was lower. Key physicochemical properties relevant to drug development were assessed: Mn(I) compounds showed lower stability in relevant tested media compared with their Re(I) counterparts and higher lipophilicity than the free ligands and the Re analogues. To gain insight into the potential mechanisms of action, the interaction with DNA and the effects on ergosterol biosynthesis in T. cruzi and L. infantum were investigated. Minimal DNA association (<1%) and moderate interaction with this target discarded DNA binding as the primary mechanism of action. In contrast, inhibition of lanosterol 14-α-demethylase (CYP51), key enzyme involved in the parasites' ergosterol biosynthetic pathway, was experimentally confirmed. Metallomic study revealed an uptake by T. cruzi of the most promising compound, fac-[Mn(CO)3(CTZ)(tmp)](PF6), more than twice that of the Re(I) analogue and preferential association to soluble proteins. Proteomic analysis of T. cruzi epimastigotes treated with the Mn(I) and Re(I) analogues showed no change in CYP51 abundance, suggesting that reduced ergosterol levels may arise from post-translational modifications of the enzyme. Raman confocal microscopy allowed us to detect effects of the most promising Mn compound in treated T. cruzi. Furthermore, the photoinduced CO release properties of both Mn and Re analogues were examined, searching for an additional and yet non-studied potential mechanism of action of metal-tricarbonyls in these trypanosomatid parasites. Collectively, the results highlight the potential of Mn(I) tricarbonyls as promising candidates for further drug development.

The quinoline moiety represents an important scaffold for the development of leishmanicidal agents. In particular, its hybridization with metal/metalloids has generated highly active compounds that are, in some cases, highly selective against leishmaniasis models. The existing leishmanicidal metal-/metalloid-quinoline compounds are mainly based on the following: (i) coordination compounds based on 8-hydroxyquinolinate; (ii) metallocene derivatives; (iii) N-heterocyclic carbene (NHC) complexes featuring a quinoline moiety. This mini-review summarizes the reported cases of leishmanicidal metal and metalloid-based quinoline compounds for each group (i–iii), focusing on the structure-property relationship from in vitro Leishmania models and mechanisms of action, in vivo experiments, and pharmacokinetic data, if available. This paper aims to describe the state of the art of inorganic medicinal chemistry for the development of selective and potent leishmanicidal agents using the quinoline moiety.

Chagas disease and Leishmaniasis, caused by Trypanosoma cruzi and Leishmania spp., respectively, are highly prevalent neglected tropical diseases (NTDs) that pose significant global health challenges. In our pursuit of effective vanadium-based therapeutics against these diseases, we previously developed several series of oxidovanadium(V) complexes featuring bidentate bioactive ligands and Schiff base tridentate ligands. The current study extends our previous research by incorporating in the same molecule, a tridentate bromo-substituted isonicotinyl hydrazone Schiff base ligand, BrIS, and a 8-hydroxyquinoline derivative (L), leading to the synthesis and comprehensive characterization of five new complexes, [VVO(BrIS-2H)(L-H)]. Most of new complexes exhibited activity in the micromolar range against the infective trypomastigote form of T. cruzi (EC50, 24h: 0.73-7.95 μM) and against L. infantum promastigotes (IC50, 5 days: 1.14-1.16 μM) and some of them showed good selectivity indexes towards the parasites (SI up to 52). Notably, the vanadium uptake by the parasites was higher for the new [VVO(BrIS-2H)(L-H)] compounds compared to [VVO(IN-2H)(L-H)] analogues previously developed, where IN is the structurally related 2-hydroxy-1-naphtaldehyde isonicotinoylhydrazone ligand, with accumulation in the soluble cell fraction. High-dose incubations resulted in trypanocidal effects and suggested the generation of reactive oxygen species (ROS). Further analysis revealed that [VVO(BrIS-2H)(L-H)] complexes induced a higher percentage of apoptosis, whereas the [VVO(IN-2H)(L-H)] series was associated with autophagic cell death. These findings highlight the potential of the [VVO(BrIS-2H)(L-H)] series as promising anti-T. cruzi agents and underscore the need for further research to optimize their therapeutic efficacy and explore their mechanisms of action.

Antimicrobial resistance is a major global problem for public health, indicating the need for the development of new anti-infective drugs, among other actions (i.e., better stewardship, diagnostics, etc.). A common strategy in medicinal chemistry is to modify existing drugs with an organometallic moiety to enhance their efficacy or overcome resistance. One notable example is ferroquine, an organometallic derivative of chloroquine. Here, we describe the design, in-depth characterization, and in vitro evaluation of seven new derivatives of the antifungal drug itraconazole (ITZ) against parasitic and fungal pathogens. ITZ was selected as a privileged scaffold because it targets ergosterol biosynthesis, which is an essential component of cell membranes in fungi and trypanosomatid parasites. While none of the compounds were active against Trypanosoma cruzi and Leishmania infantum, the ferrocenyl derivatives proved to be 1.5- to 1.9-fold more potent than ITZ toward Trypanosoma brucei. Of particular interest, all of the compounds exhibited high antifungal activity against the azole-susceptible clinical isolates. Furthermore, the ferrocenyl-containing compound was the most active against Aspergillus. Despite showing 10-fold lower activity than ITZ, these organometallic derivatives constitute an interesting starting point for further pharmacomodulation since we confirmed that they blocked the ERG11 enzyme, the main target of azoles.

In the search for a more effective chemotherapy for the treatment of Chagas’ disease, caused by Trypanosoma cruzi parasite, the use of gold compounds may be a promising approach. In this work, four gold(I) compounds [AuCl(HL)], (HL = bioactive 5-nitrofuryl containing thiosemicarbazones) were studied. The compounds were theoretically characterized, showing identical chemical structures with the metal ion located in a linear coordination environment and the thiosemicarbazones acting as monodentate ligands. Cyclic voltammetry and Electron Spin Resonance (ESR) studies demonstrated that the complexes could generate the nitro anion radical (NO2−) by reduction of the nitro moiety. The compounds were evaluated in vitro on the trypomastigote form of T. cruzi and human cells of endothelial morphology. The gold compounds studied showed activity in the micromolar range against T. cruzi. The most active compounds (IC50 of around 10 μM) showed an enhancement of the antiparasitic activity compared with their respective bioactive ligands and moderate selectivity. To get insight into the anti-chagasic mechanism of action, the intracellular free radical production capacity of the gold compounds was assessed by ESR and fluorescence measurements. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and redox cycling processes were characterized. The potential oxidative stress mechanism against T. cruzi was confirmed.

Trypanosomatid parasites and fungi cause highly prevalent diseases. Ergosterol plays a crucial role in the structure and normal function of the membrane of these microorganisms. It is absent in mammals. Many enzymes of the ergosterol biosynthesis route have been recognized as molecular targets for drugs. Currently, a variety of organic drugs that interfere with sterol biosynthesis are employed to treat fungal infections, and some of them have been proposed as potential treatments for trypanosomiasis. Coordinating these organic drugs to metal ions may positively impact the biological performance by altering relevant physicochemical properties. Additionally, their organometallic derivatization could improve the effectiveness. This comprehensive review aims to highlight the considerable promise of metal-based compounds as inhibitors of essential pathways or key enzymes of these microorganisms, with focus on the ergosterol biosynthesis pathway. Additionally, bioactive metal compounds that have demonstrated experimental efficacy in acting on enzymes within this pathway although not designed for this purpose were included. The current state of the art demonstrates the impressive but still underexplored potential of these metal-based compounds for treating fungal and trypanosomatid infections.

Searching for new prospective drugs against Chagas disease (American trypanosomiasis) and Leishmaniasis, a series of five heteroleptic vanadium compounds, [VIVO(L-H)(mpo)], where L are 8-hydroxyquinoline derivatives and mpo is 2-mercaptopyridine N-oxide, are synthesized and characterized. Comprehensive characterizations are conducted in solid state and in solution. The compounds are evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi and in promastigotes of Leishmania infantum, alongside on VERO cells, as a mammalian cell model. The compounds exhibit activity against both forms of T. cruzi and promastigotes of L. infantum, with the trypomastigote infective stage of T. cruzi displaying the highest sensitivity. The most selective vanadium compound [VIVO(L2-H)(mpo)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, globally shows adequate selectivity towards the parasite and was selected to carry out further in-depth biological studies. [VIVO(L2-H)(mpo)] significantly impacted the infection potential of cell-derived trypomastigotes and hindered the replication of the T. cruzi amastigote form. Low total vanadium uptake by T. cruzi parasites and preferential accumulation in the soluble proteins fraction, with negligible localization in the DNA fraction, are determined. A trypanocide effect is observed across various concentrations of the compound. The generation of oxidative stress and the induction of mitochondria-dependent apoptosis are proposed as the main mechanisms of the parasite’s death by the VIVO compounds. Both theoretical predictions and experimental data support the hypothesis that inhibiting the parasite-specific enzyme NADH-fumarate reductase activity plays a crucial role in the trypanocidal action of these complexes. Globally, [VIVO(L-H)(mpo)] complexes could be considered interesting anti-T. cruzi agents that deserve further research.

Cancer and infection diseases pose severe threats to public health worldwide stressing the need for more effective and efficient treatments. Thus, the search for broad-spectrum activity drugs seems justifiable and urgent. Herein, we investigate the anticancer and antitrypanosomatid (anti-Trypanosoma cruzi) activities of eight monoanionic metal bis(dithiolene) complexes, [Ph4P][M(R-thiazdt)2] with Mn+ = Au3+, Pt2+, Pd2+, Ni2+, containing N-alkyl-1,3-thiazoline-2-thione dithiolene ligands (R-thiazdt) with different alkyl groups (R = Et, tBu). Compared to auranofin (AF) and cisplatin (CP), two reference drugs in clinical use, all complexes showed high anticancer activities against A2780 ovarian cancer cells (IC50 values of 0.6-3.8 μM) some also being able to overcome CP resistance in A2780cisR cells. The selectivity index (SI), the IC50 values on normal cells (HDF) vs. A2780 cells, indicated good anticancer specificity (SI > 3) for most of the complexes but with clinical relevance for [Ph4P][Pd(tBu-thiazdt)2] (SI = 10). All complexes showed relevant antitrypanosomatid activities (IC50 values of 2.6-5.8 μM) some even exhibiting lower IC50 values than the reference drug nifurtimox (NFX). The mechanism of cell death seemed to be mediated mainly by the formation of reactive oxygen species (ROS), although to lesser extent for the gold complexes but superior to AF. Although ROS play a role in the main apoptotic pathways, cell death by apoptosis was not evident as shown by the caspase-3/7 assay and the morphological cell features studies by electron microscopy (SEM). Results obtained evidenced that [Ph4P][Pt(tBu-thiazdt)2] and [Ph4P][Pd(tBu-thiazdt)2] complexes might have potential as novel anticancer and antitrypanosomatid agents as alternatives to current therapeutics.

Metallomics is an emerging area of omics approaches that has grown enormously in the past few years. It integrates research related to metals in biological systems, in symbiosis with genomics and proteomics. These omics approaches can provide in-depth insights into the mechanisms of action of potential metallodrugs, including their physiological metabolism and their molecular targets. Herein, we review the most significant advances concerning cellular uptake and subcellular distribution assays of different potential metallodrugs with activity against Trypanosma cruzi, the protozoan parasite that causes Chagas disease, a pressing health problem in high-poverty areas of Latin America. Furthermore, the first multiomics approaches including metallomics, proteomics, and transcriptomics for the comprehensive study of potential metallodrugs with anti-Trypanosoma cruzi activity are described.

Introduction: Glioblastoma is a brain cancer difficult to treat but recently mixed-ligand vanadium(V) Schiff base/catecholato complexes have exhibited high in vitro anti-proliferative activity. Hence, we explored the activity of [VVOL1L2], which contains two iron chelating ligands, 2-hydroxy-1-naphthylaldehyde iso-nicotinoyhydrazone (L1H2) and clioquinol (L2H). This complex was previously reported to be very effective against Trypanosoma cruzi, the causative agent of Chagas disease. These studies explored the possibility that a compound with efficacy against Trypanosoma cruzi also has efficacy against human glioblastoma cancer cells. Since [VVOL1L2] was poorly soluble in water and the clioquinol ligand dissociated from the complex upon addition to an aqueous environment, an understanding of the speciation was very important to interpret its biological activity.Methods: Stability studies in cell media were followed by UV/Vis spectroscopy to determine speciation of relevance to the in vitro anti-proliferative activity of the complex with T98G glioblastoma cells, which was also measured in the absence and presence of Fe(III).Results and Discussion: The current work demonstrated that the mixed-ligand vanadium coordination complex had high in vitro anti-proliferative activity against the human glioblastoma (T98G) cell line. The enhanced anti-proliferative effects of the mixed-ligand vanadium complex against T98G cells could be due to either hydrolysis of complex and release of the toxic clioquinol, or the rapid uptake of the lipophilic complex prior to hydrolysis. The speciation studies showed that at least part of the potent toxicity of the mixed-ligand coordination complex stemmed from release of the bioactive clioquinol ligand from the complex, which depended on whether Fe(III) was present. The studies also showed that the [VV(O)2 (L1H)] coordination complex was the most potent complex that remained intact and, hence, the complex that is the most biological active. Thus, future development of complexes should focus on the one-ligand intact complexes or making any mixed-ligand complex more water soluble, stable in aqueous solution, or designed to be rapidly taken up by diseased cells prior to hydrolysis.

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.

Human African trypanosomiasis (HAT, sleeping sickness) and American trypanosomiasis (Chagas disease) are endemic zoonotic diseases caused by genomically related trypanosomatid protozoan parasites (Trypanosoma brucei and Trypanosoma cruzi, respectively). Just a few old drugs are available for their treatment, with most of them sharing poor safety, efficacy, and pharmacokinetic profiles. Only fexinidazole has been recently incorporated into the arsenal for the treatment of HAT. In this work, new multifunctional Ru(II) ferrocenyl compounds were rationally designed as potential agents against these pathogens by including in a single molecule 1,1'-bis(diphenylphosphino)ferrocene (dppf) and two bioactive bidentate ligands: pyridine-2-thiolato-1-oxide ligand (mpo) and polypyridyl ligands (NN). Three [Ru(mpo)(dppf)(NN)](PF6) compounds and their derivatives with chloride as a counterion were synthesized and fully characterized in solid state and solution. They showed in vitro activity on bloodstream T. brucei (EC50 = 31-160 nM) and on T. cruzi trypomastigotes (EC50 = 190-410 nM). Compounds showed the lowest EC50 values on T. brucei when compared to the whole set of metal-based compounds previously developed by us. In addition, several of the Ru compounds showed good selectivity toward the parasites, particularly against the highly proliferative bloodstream form of T. brucei. Interaction with DNA and generation of reactive oxygen species (ROS) were ruled out as potential targets and modes of action of the Ru compounds. Biochemical assays and in silico analysis led to the insight that they are able to inhibit the NADH-dependent fumarate reductase from T. cruzi. One representative hit induced a mild oxidation of low molecular weight thiols in T. brucei. The compounds were stable for at least 72 h in two different media and more lipophilic than both bioactive ligands, mpo and NN. An initial assessment of the therapeutic efficacy of one of the most potent and selective candidates, [Ru(mpo)(dppf)(bipy)]Cl, was performed using a murine infection model of acute African trypanosomiasis. This hit compound lacks acute toxicity when applied to animals in the dose/regimen described, but was unable to control parasite proliferation in vivo, probably because of its rapid clearance or low biodistribution in the extracellular fluids. Future studies should investigate the pharmacokinetics of this compound in vivo and involve further research to gain deeper insight into the mechanism of action of the compounds.

The search for new anti-infectives based on metal complexes is gaining momentum. Among the different options taken by researchers, the one involving the use of organometallic complexes is probably the most successful one with a compound, namely ferroquine, already in clinical trial against malaria. In this study, we describe the preparation and in-depth characterization of 10 new (organometallic) derivatives of the approved antifungal drug fluconazole. Our rationale is that the sterol 14α-demethylase is an enzyme part of the ergosterol biosynthesis route in Trypanosoma and is similar to the one in pathogenic fungi. To demonstrate our postulate, docking experiments to assess the binding of our compounds with the enzyme were also performed. Our compounds were then tested on a range of fungal strains and parasitic organisms, including the protozoan parasite Trypanosoma cruzi (T. cruzi) responsible for Chagas disease, an endemic disease in Latin America and ranked as the third most prevalent parasitic disease after malaria and schistosomiasis. Of high interest, the most two potent compounds of the study on T. cruzi that contain a ferrocene or cobaltocenium were found to be harmless for an invertebrate animal model, namely Caenorhabditis elegans (C. elegans), without affecting motility, viability or development.

Chagas' disease (American Trypanosomiasis) is an ancient and endemic illness in Latin America caused by the protozoan parasite Trypanosoma cruzi. Although there is an urgent need for more efficient and less toxic chemotherapeutics, no new drugs to treat this disease have entered the clinic in the last decades. Searching for metal-based prospective antichagasic drugs, in this work, multifunctional Re(I) tricarbonyl compounds bearing two different bioactive ligands were designed: a polypyridyl NN derivative of 1,10-phenanthroline and a monodentate azole (Clotrimazole CTZ or Ketoconazol KTZ). Five fac-[Re(CO)3(NN)(CTZ)](PF6) compounds and a fac-[Re(CO)3(NN)(KTZ)](PF6) were synthesized and fully characterized. They showed activity against epimastigotes (IC50 3.48-9.42 μM) and trypomastigotes of T. cruzi (IC50 0.61-2.79 μM) and moderate to good selectivity towards the parasite compared to the VERO mammalian cell model. In order to unravel the mechanism of action of our compounds, two potential targets were experimentally and theoretically studied, namely DNA and one of the enzymes involved in the parasite ergosterol biosynthetic pathway, CYP51 (lanosterol 14-α-demethylase). As hypothesized, the multifunctional compounds shared in vitro a similar mode of action as that disclosed for the single bioactive moieties included in the new chemical entities. Additionally, two relevant physicochemical properties of biological interest in prospective drug development, namely lipophilicity and stability in solution in different media, were determined. The whole set of results demonstrates the potentiality of these Re(I) tricarbonyls as promising candidates for further antitrypanosomal drug development.