Edgar Del Carpio1*†
Lino Hernández2†Vito Lubes2†
Francisco Jourdan3
Hugo Cerecetto3,4†
Gonzalo Scalese5,6†
Dinorah Gambino5*†
Angel H. Romero3*†- 1Unidad de Química Medicinal, Facultad de Farmacia, Escuela “Dr. Jesús María Bianco”, Universidad Central de Venezuela (UCV), Caracas, Venezuela
- 2Departamento de Química, Universidad Simón Bolívar (USB), Caracas, Venezuela
- 3Grupo de Química Orgánica Medicinal, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
- 4Área de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República Montevideo, Montevideo, Uruguay
- 5Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay
- 6Área Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay
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.
1 Introduction
Leishmaniasis, one of the most important neglected tropical diseases, is caused by the protozoan intracellular parasite of Leishmania spp (Murray et al., 2005). The disease is present in 98 countries, registering between 0.7 and 1.3 million new cases and approximately 40,000 deaths annually (Kumar, 2021; World Health Organisation, 2023).
Regarding treatment, there are no vaccines, and the therapeutic alternatives are ineffective. Current chemotherapy is primarily based on pentavalent antimonials (e.g., glucantime and pentostam) and pentamidine, which are not approved by the Food and Drug Administration (FDA), and other FDA-approved drugs such as amphotericin B and miltefosine (Aronson et al., 2016; Kumari et al., 2022). However, in general, these commercial drugs present significant side effects (affecting the heart, liver, and kidneys), high cost, low therapeutic efficacy, and prolonged treatment duration (30–60 days) (Nih.gov, 2022). Combination therapies with multiple drugs (Mota et al., 2024; Sundar et al., 2024), development of liposomes and nanoparticles for controlled drug release (Mendes et al., 2020), and repositioning of drugs have been used as emerging therapeutic strategies to improve the efficiency and therapeutic arsenal (Chartlon et al., 2017). Alternatively, the Drugs for Neglected Diseases initiative, (2023) (DNDi) and European and Asian agencies have made great investments in the discovery of new leishmanicidal agents; however, the failure rate has been too high (e.g., from DNDi data, only 20 of 4,200,000 tested) (DNDi, 2023). To develop new effective, selective, and safe leishmanicidal agents, it is necessary to go beyond the classic concept of medicinal chemistry, focusing on key aspects of parasite survival within macrophages (Romero and Delgado, 2024).
Because metal ions play an important role in many biological processes, the use of metal-containing compounds to modulate parasite biological processes has gained relevance as a therapeutic alternative for the design of leishmanicidal agents (Medina-Franco et al., 2022; Gambino and Otero, 2018; Gambino, 2024; Jimenez-Falcao et al., 2024; Hemmert et al., 2025; Tahghighi, 2014). Metal binding can promote the following: (i) DNA interaction; (ii) inhibition of key enzymes; (iii) oxidative stress; (iv) affectation of cell parasite integrity (Rosa et al., 2021; Navarro and Visbal, 2015; Crans and Kostenkova, 2020; Karges et al., 2021; Kostenkova et al., 2022; Fricker et al., 2008; Scalese et al., 2024b; Colotti et al., 2013), among other effects. Because native strains of Leishmania have developed arsenic reductase enzymes (Mukhopadhyay et al., 2009), the introduction of reducible elements into leishmanicidal agents can be of great relevance to induce a redox-active pathway within the parasite (Mushtaq et al., 2016; Ouellette et al., 2004). For that reason, the antimonials glucantime or pentostam are among the most representative leishmanicidal agents. Beyond the semimetal Sb(V), Bi(III)/Bi(V) (Duffin et al., 2017; Islam et al., 2014; Fiore-Apuzzo et al., 2021) and transition metals such as Fe, Ru, Re, Mn, Pd, Pt, Rh, Ir, and Au (Ong et al., 2018; Gambino and Otero, 2018; Gambino, 2024; Rosa et al., 2021; Braga et al., 2022) have been used for the development of leishmanicidal agents. Aside from the redox-active element, the choice of the organic ligand plays a key role, and active scaffolds are typically chosen in the design of metal and metalloid-based compounds.
Different organic ligands, including quinolines, salicylaldimines, thiosemicarbazones, and azoles, have been used for the generation of prospective metallodrugs in which the combination enhances the activity and selectivity compared to parent ligands (Gambino and Otero, 2018; Mbaba et al., 2020). In particular, the electron-donor-moiety-substituted quinoline represents a highly convenient scaffold for the design of leishmanicidal agents because i) this structure can be involved in key aspects of Leishmania survival during infection process such as parasite mitochondrial dysfunction, accumulation into the phagolysosome, and immunostimulating roles (Romero et al., 2019; Silva et al., 2023; Romero and Delgado, 2024; Yaluf et al., 2025; Avanzo et al., 2025) as well as ii) their multiple feasible synthetic ways (Delgado et al., 2025). The present mini-review aims to provide a general compilation of metal and metalloid-based quinoline compounds as leishmanicidal agents, focusing on biological response against in vitro models (promastigote form and/or amastigote form), and limited in vivo, structure–activity, and mechanistic aspects. The existing leishmanicidal quinoline-metal compounds are mainly based on the following three structures: (i) coordination compounds based on 8-hydroxyquinolinate; (ii) metallocenes bearing a quinoline moiety; (iii) N-heterocyclic carbene (NHC) complexes bearing a quinoline moiety. Herein, to facilitate the analysis, we revised this classification accordingly.
2 Metal- and metalloid-based quinoline compounds
2.1 Coordination compounds based on 8-hydroxyquinolinates
Between 2020 and 2021, Duffin prepared a series of Sb(V) and Ga(III) 8-hydroxyquinolinate complexes using different 8-quinolinol substituted ligands (L1–L6) to evaluate their activities against promastigotes and amastigotes of L. major (Figures 1A,B). Beginning with Sb(V) complexes, six heteroleptic Sb(V) 8-hydroxyquinolinolate compounds, ([SbPh3(OH)(L-H)]), were synthesized and characterized (Figure 1A) (Duffin et al., 2021). Single crystal X-ray analysis revealed a distorted octahedral geometry with an O-Sb-O angle ranging from 164.3° to 174.0°. Against the promastigote model, the six complexes exhibited similar leishmanicidal responses, displaying IC50 values between 2.03 µM and 3.39 μM. Compounds [SbPh3(OH)(L4-H)], [SbPh3(OH)(L5-H)], and [SbPh3(OH)(L6-H)] showed the highest selectivity indexes (S.I.) (∼16 based on fibroblast cytotoxicity and antipromastigote activity). Against an amastigote model (infection between 15% and 20%) and under a compound treatment (10 μM), the [SbPh3(OH)(L4-H)] and [SbPh3(OH)(L5-H)] reduced the infection to 4.25% and 2.25%, respectively, which was comparable to that obtained under amphotericin B treatment (3.5%). The remaining Sb-quinoline compounds reduced the infection between 7% and 9%.
Figure 1. General structure and leishmanicidal response of Sb (V) (A), Ga(III) (B), and vanadium (C) complexes featuring 8-hydroxyquinolinates.
Regarding Ga(III) complexes, four monomethylgallium (III)([Ga(CH3)(L-H)2]) and four other dimethylgallium(III) ([Ga(CH3)2(L-H)]) compounds containing a halogen-substituted 8-hydroxyquinolinate ligand (L2, L3, L4, and L5, Figure 1A) were prepared (Duffin et al., 2020). Single-crystal X-ray diffraction showed that the monomethyl complexes were characterized by adopting a five-coordinate trigonal bipyramidal structure, whereas the dimethyl complexes showed a four-coordinate tetrahedral geometry (Figure 1B). [GaCH3(L3-H)2], [GaCH3(L4-H)2], and [GaCH3(L5-H)2] complexes were not tested due to their poor solubility. Against the promastigote model, complexes [Ga(CH3)2(L2-H)] and [GaCH3(L2-H)2] exhibited the strongest leishmanicidal response with IC50 values of 2.45 µM and 1.11 µM, respectively, whereas the remaining compounds displayed IC50 values between 7 µM and 13 µM. Against the amastigote model and under 10 µM treatment, complexes [Ga(CH3)2(L2-H)] and [GaCH3(L2-H)2] showed superior activity, reducing the infection to 5.3% and 3.5%, respectively, which is comparable with the leishmanicidal response of amphotericin B (3.5%). The [GaCH3(L2-H)2] complex showed the best S.I. (Scalese et al., 2019), being clearly more selective than Sb(V) analogs (S.I. ∼ 16). These compounds showed good stability at lysosomal pH (Crans and Kostenkova, 2020; Colotti et al., 2013), facilitating accumulation and chemical stability in phagolysosomes (Romero and Delgado, 2022). Overall, the antimonium and gallium coordination improved the leishmanicidal response compared to the parent 8-hydroxyquinolines. Meanwhile, a qualitative structure–activity analysis revealed that polyhalogenated quinolinates bearing heavy halogens such as bromide and iodide led to more active and selective quinolinate-antimonium and -gallium complexes. Regarding the mechanism of action, either Sb(V)- or Ga(III)-8-hydroxyquinolinate complexes promoted the production of ROS in cytosolic macrophages.
Oxidovanadium(IV) and (V) species have demonstrated versatility for drug design due to their diverse therapeutic effects (Del Carpio et al., 2018; Hernández et al., 2022). Gambino´s group synthesized and characterized two groups of V(IV)- and V(V)-8-hydroxyquinolinate complexes, and biologically evaluated them against L. infantum promastigotes using 51V-NMR, EPR, ESI-MS, and microanalysis. The first group consisted of a series of V(IV) and V(V) bis(8-hydroxyquinolinate) complexes to give five [VIVO(L′-H)2] and five [VVO(OCH3)(L′-H)2] complexes using 8-hydroxyquinolinate ligands L1´–L5´ (Figure 1C) (Scalese et al., 2019).
Vanadium complexes (IC50 = 2–9 μM, S.I. = 4.8–24.7) were slightly less active and selective than parent 8-quinolinol ligands (IC50 = 2–3 μM, S.I. = 5.3–55.2) (Figure 1C). For L2′, V(IV)- and V(V)-complexation barely improved both the leishmanicidal response and selectivity of the 8-quinolinol L2′ from an IC50 of 3.2 µM (S.I. = 20.2) to an IC50 of 2.07 µM (S.I. = 24.7) and 2.85 µM (S.I. = 21.4) for [VIVO(L2′-H)2] and [VVO(OCH3)(L2′-H)2] complexes, respectively. V(IV) complexes were, in general, more active and selective than their V(V) counterparts. Gambino and Otero, (2018) reported the leishmanicidal potential of a second group of heteroleptic V(IV) complexes bearing a 8-hydroxyquinolinate (L1′-L4′ and L6′) and 2-mercaptopyridine N-oxide (mpo), [VIVO(L′-H)(mpo)] (Figure 1C) (Scalese et al., 2024a). The new vanadium complexes (IC50 = 0.65–1.56 µM) were significantly more active than their parent 8-quinolinols (IC50 = 0.73–3.20 µM) and V(IV) and V(V) bis(8-quinolinate) complexes (IC50∼2–9 µM), although they exhibited a higher toxicity and lower selectivity (S.I. = 1–18.6) than quinolinols (S.I. = 5.3–34) and vanadium-bis(8-hydroxyquinolinate) complexes (S.I. = 4.8–24.7). Among the [VIVO(L′-H)(mpo)] complexes, [VIVO(L1′-H)(mpo)] and [VIVO(L2′-H)(mpo)] were the most active and selective. Even though incorporating the mpo ligand increases the leishmanicidal response, it compromises the selectivity compared with vanadium-bis(8-hydroxyquinolinate) complexes. Further experiments have shown that vanadium complexes promote late apoptosis/necrosis.
2.2 Metallocenes bearing a quinoline moiety
Most of these examples are focused on chloroquine analogs bearing a ferrocenyl moiety along the alkylamino lateral chain (Figure 2). Due to the redox properties of the ferrocenyl, that motif favors a high activity against intracellular amastigotes of Leishmania spp. (Vale-Costa et al., 2013; Mbaba et al., 2022). The redox activity of the ferrocenyl may also alter parasite metabolism, induce oxidative stress, or interfere with parasite replication or transcription (Kondratskyi et al., 2017). In addition, including the ferrocenyl moiety into the lead structure may favor water solubility, reducing the toxic side effects and improving bioaccumulation (Van Staveren and Metzler-Nolte, 2004).
Figure 2. Structure and leishmanicidal activity of quinoline featuring a metallocene moiety (A–G).
Our compilation begins with the example reported by Pomel et al. (2015) using ferroquine (Figure 2A). Ferroquine is a chloroquine analog bearing a ferrocenyl group along the dialkyldiamino chain. Ferroquine was found to be inactive at 20 μM against intracellular amastigotes of L. donovani, in contrast with chloroquine (IC50 = 0.5 μM against L. donovani amastigote) (Pomel et al., 2012). Thus, incorporating the ferrocenyl moiety into the middle region of the dialkyldiamino chain appears to be ineffective.
In 2012, Nordlander and co-workers prepared a series of chloroquine analogs bearing a cymantrenyl-, [CpMn(CO)3], or cyrhetrenyl-moiety, [CpRe(CO)3], at the end of the alkylamino lateral chain (Figure 2B) (Glans et al., 2012). The compounds showed a discrete leishmanicidal response against L. major promastigotes, displaying IC50 values around 10.2 µM. Another feature that limits the potential of the metallocenes 1–3 is their high toxicities on J774.1 macrophages (CC50 = 4.6–9.1 µM), which implies S.I. values lower than 1. Therefore, the cymantrenyl and cyrhetrenyl moieties offer limited potential for enhancing the leishmanicidal activity and selectivity of chloroquine analogs.
Between 2015 and 2016, Adhikari´s group prepared a series of 13 chloroquine analogs featuring a ferrocenyl moiety at the end of the alkylamino lateral chain and a triazolyl moiety to replace the dialkylamino group for evaluation against Leishmania spp. (Figure 2C) (Yousuf et al., 2015; Yousuf et al., 2016). Among the 13 derivatives, compounds 4–7 were identified as the most active against L. donovani promastigotes (Figure 2C), although displaying a discrete response (IC50∼22–28 µM for compounds 5-7 and IC50 = 15.3 µM for compound 4). An extra aryl/heteroaryl ring in the ferrocenyl-quinoline compound did not enhance the leishmanicidal response compared to compound 4. These drugs had similar leishmanicidal responses to leishmanicidal reference drugs miltefosine (IC50 = 21 µM), chloroquine (IC50 = 30 µM), and ferroquine (IC50 = 20 µM) against a L. donovani promastigote. Compound 4 was identified as the most promising compound against the amastigote strain, being able to inhibit the amastigote proliferation in 50% at 0.5 µM without cytotoxicity toward murine splenocytes (at 32 µM treatment), which revealed the high specificity of this type of quinolinic compound toward the amastigote form over the promastigote form. Compounds 5–7 displayed IC50 values between 8 µM and 16 µM. Further studies showed that compound 4 promoted: (i) changes in the mitochondrial depolarization potential into promastigotes; (ii) changes promastigote morphology including loss of flagella and appearance of pores in cell membrane; (iii) death via apoptosis; (iv) depletion of GSH; (v) DNA fragmentation in promastigotes; (vi) increase of ROS level; (vii) increase of NO production in infected macrophages model; (viii) increase of the levels of lipid peroxides. Compound 4 acts through an oxidative pathway, initiated by lipid peroxidation, followed by a decrease in protein content and changes in the nature of the lipidic membranes. The latter leads to a loss of mitochondrial membrane potential, leading to apoptosis in L. donovani promastigotes. The release of NO in the infected macrophage model could suggest that the compound can also upregulate the innate immune response.
To improve the water solubility of compound 4, Adhikari´s group prepared a series of four novel flexible and water-soluble ferrocenyl quinolines with N-quaternization, 8–11 (Figure 2D) (Mukherjee et al., 2020). Against the intracellular amastigote of L. donovani, compound 8 displayed the best leishmanicidal response with an IC50 value of 0.50 μM, whereas compounds 9, 10, and 11 displayed IC50 values of 2.4 µM, 1.0 µM, and 5.1 μM, respectively. Their activities were higher than those of amphotericin B (IC50 = 26.0 μM), Glucantime (IC50 = 170 μM), miltefosine (IC50 = 13.6 μM), and paromomycin (IC50 = 8 μM). Compound 8 was evaluated for in vivo efficacy and mechanistic assays, demonstrating a significant reduction of parasitemia with a dose-dependent response under oral administration. Further studies showed that the ferrocenyl quinoline 8 stimulated the secretion of Th1 with either oral or intramuscular administration and promoted the expression of key pro-inflammatory cytokines, IL-6, IL-12, TNF-α, and IL-1β for the in vivo model. A significant increase in the level of NO in in vivo models was found. In addition, compound 8 reduced the expression of key enzymes such as γ-glutamylcysteine synthetase, glutathione synthetase, ornithine decarboxylase, and trypanothione reductase. Additionally, compound 8 showed good pharmacokinetic/pharmacodynamic and oral bioavailability profiles (Cmax of 581.8 ng/mL and 287.8 ng/mL, t1/2 of 7.7 h and 15.0 h, AUC0-inf of 14,060.2 g/mL×h and 8077.2 ng/mL×h and a maximum concentration in the liver of 214.7 µg/g and 106.4 μg/g under oral and intramuscular administration, respectively). Compound 8 did not interfere with the expression of phase I and phase II detoxification enzymes in the host liver, making it a good candidate for further preclinical studies.
Beyond the chloroquine scaffold, Vale-Costa prepared a series of thirty primaquine analogs bearing a ferrocene group at the end of the 8-alkylamino lateral chain (Figure 2E) (Vale-Costa et al., 2012) to evaluate against promastigotes and amastigotes of L. infantum. Compounds 12–15 showed a good leishmanicidal profile. Against the promastigote model, complexes 13 and 15 exhibited the best antipromastigote response with IC50 values of 4.9 µM and 11.5 µM, respectively, which were lower than that found for primaquine (IC50 = 26.5 µM) and in the same range as sitamaquine (IC50 = 7.4 µM) and miltefosine (IC50 = 14.4 µM). Compound 12 showed a discrete response (IC50 = 22.7 µM), whereas compound 14 was not active (IC50 > 80 µM). Interestingly, the most active, compound 13, was the most toxic compound (CC50 = 6.8 µM), whereas the other three compounds, 12, 14, and 15, and primaquine displayed CC50 responses higher than 80 µM. Compounds 12, 14, and 15 were evaluated against the amastigote model, finding that only compounds 14 and 15 promoted a significant reduction of infection in infected macrophages by approximately 96% and 77%, respectively, upon a compound treatment of 40 µM. These results demonstrated that the incorporation of the ferrocenyl moiety improved the leishmanicidal response of primaquine, which only showed a reduction of 50.8% under the same conditions. Further assays are needed to evaluate the potential of compounds 14 and 15.
Another non-chloroquine analog example was described by Madureira and co-workers. They prepared a series of eight 8-O, 4-, 3-, 6-, and 8-aminoquinolines connected to a ferrocene group through ester or amide bridges (Quintal et al., 2013) (Figure 2F). Compounds showed a weak leishmanicidal response against promastigotes of L. infantum, giving high IC50 values (64–269 µM). Only a quinoline–ferrocene derivative, compound 16, was tested against infected macrophages, displaying a significant reduction of infection with an IC50 value of 5.2 µM, which implies an S.I. value of 16.6 that was significantly better than that of the control drug miltefosine (6.1). A comparison with primaquine analogs highlighted that the presence of a longer alkylamino chain between the quinoline core and the ferrocenyl group is essential for generating a more potent and selective agent.
Recently, Gambino (2024) reported the leishmanicidal activity of novel multifunctional Ru(II) ferrocenyl compounds (18–21) featuring a single 1,1′-bis (diphenylphosphino) ferrocenyl (dppf), a 8-hydroxyquinolinyl ligand (22–23) and a polypyridyl ligand (Figure 2G) (Rivas et al., 2022). Selected 8-hydroxyquinolinyl ligands were 5-chloro-7-iodo-8-hydroxyquinoline (L7) and 5,7-diiodo-8-hydroxyquinoline (L8), and selected polypyridyl ligands were 3,4,7,8 tetramethylphenanthroline and 2,2′-bypyridine. These new Ru-Fe compounds enhanced the leishmanicidal effect against the L. infantum promastigote by more than 2-fold compared to the parent 8-quinolinols, but they were considerably more toxic on J774.1 macrophages, implying S.I. values between 0.7 and 4.9. Only compound 21, which features a chloride as counterion, showed an S.I. of 4.9 derived from an IC50 of 1.0 µM against promastigote L. infantum.
2.3 N-heterocyclic carbene complexes featuring quinoline moiety
Paloque et al. reported in 2015 a series of four organometallic complexes of Au(I) and one of Ag(I) bearing quinoline-functionalized N-heterocyclic carbenes (NHC) as ligands (Paloque et al., 2015). In general, the Au(I) NHC complexes 24–26 displayed IC50 values against L. infantum promastigotes between 0.4 µM and 1.5 µM, whereas the Ag(I) NHC complex 27 showed a higher IC50 value of 9.37 µM (Figure 3A). All four Au-NHC compounds exhibited some toxicity against macrophages with CC50 values lower than 9 µM. Only the Au(I) NHC complexes 24, 25, and 26 were selected for evaluation against the amastigote model due to their higher selectivity indexes of 5.3, 6.2, and 3.0, respectively. Against the amastigote model, the Au(I) NHC complexes 24, 25, and 26 displayed IC50 values of 0.40 µM, 0.96 µM, and 0.24 µM, respectively, which implies S.I. values of 5.2, 9.8, and 5.4, respectively. These selectivities were lower than those of miltefosine (IC50 = 4.17 µM, S.I. = 37.3) and amphotericin (IC50 = 0.07 µM; S.I. = 49.9) on amastigotes.
Figure 3. Leishmanicidal response of Au(I)/Ag(I)-NHC complexes bearing a 2-quinoline moiety 24–27 (A) and 26, 28–30 (B), and (C) N-quinolin-8-yl-arylsulfonamides copper(II) and zinc(II) complexes (33–36) from quinoline ligands 31–32.
In 2018, Zhang described a series of three new NHC complexes of Au(I) 28–30 bearing a quinoline moiety and a lipophilic chain (e.g., benzyl, 2,4,6-trimethylphenyl, or 4-methylthiophenyl) connected at the imidazolium nitrogens (Zhang et al., 2018) (Figure 3B). Compound 26 was also included in that study. Compounds exhibited a moderate leishmanicidal response against promastigotes with IC50 values between 5 µM and 11 µM. These compounds displayed similar IC50 concentrations against axenic amastigotes (0.68–1.17 µM). Cytotoxicity on J774.1 macrophages showed that compound 26 was the most promising candidate with an S.I. value of 15.2 from a CC50 value of 10.76 µM. Similarly, their activities and selectivities were lower than those of miltefosine (IC50 = 0.66 µM, S.I. = 71.8) and amphotericin (IC50 = 0.05 µM; S.I. = 24.1) against axenic amastigotes. It seems that a more lipophilic chain at imidazolium, in particular, the 2,4,6-trimethylphenyl one, further compromises the selectivity.
Beyond these three types of structures, an exceptional case of a series of N-quinolin-8-yl-arylsulfonamides copper and zinc complexes (Everson da Silva et al., 2010) can be found in the literature. That report described the preparation of eight Zn- or Cu-complexes using four types of N-quinolin-8-yl-arylsulfonamides, where the aryl moiety consisted of 8-(N,N-dimethylamino) naphthyl and 4-bromo-, 3,4-dichloro-, 3,5-difluorophenyl. The compounds, ligands, and complexes (some selected cases 31–36 are shown in Figure 3C) were evaluated against promastigote L. braziliensis and L. chagasi promastigotes, finding that only the copper complexation of the N-quinolin-8-yl-(2′,4′-dichlorophenyl) sulfonamide provided a potent and selective agent 34 giving IC50 values of 2.59 µM and 2.86 µM against these Leishmania species, respectively. That complexation significantly enhanced the leishmanicidal effect compared with the parent quinoline 31. Compound 34 displayed an IC50 value of 0.35 µM against intracellular amastigotes of L. braziliensis. The zinc and copper complexation of N-quinolin-8-yl-(3′,5′-difluorophenyl) sulfonamide and N-quinolin-8-yl-(4′-bromophenyl) sulfonamide did not improve the leishmanicidal effect and increased the cytotoxicity on Vero cells, generating less selective compounds than the parent quinolines. Moreover, the complexation of N-quinolin-8-(8′-N,N-dimethylaminonaphthyl) sulfonamide yielded inactive compounds (IC50 > 100 µM).
3 Conclusion
This mini-review provided a general overview of the state of the art in developing leishmanicidal metal and metalloid compounds based on quinolines. As described, the leishmanicidal quinoline-metal compounds are mainly based on: (i) Sb(V), Ga(III), or V(IV/V) bearing 8-hydroxyquinolinates as a ligand; (ii) chloroquine or primaquine analogs bearing a ferrocenyl moiety at the alkylamino chain; (iii) quinolines bearing an Au-NHC moiety. From the first group, three key remarks were extracted: (i) dihalogenated-quinolinols generated the most selective and active complexes, (ii) Ga(III) generated the most selective and least toxic agent compared to the Sb(V) and V(IV/V) analogs, and (iii) this type of complex is able to promote ROS production. From the second group, it should be noted that: (i) the ferrocenyl moiety generated more active and selective agents than group VII-metals (Mn, Re) cymantrenyl and cyrhetrenyl organometallic derivatives; (ii) the incorporation of the ferrocenyl moiety at the terminal position of the dialkyldiamino chain in chloroquine or primaquine analogs improves selectivity more than its incorporation at the middle region; (iii) more promising agents were found by using active quinoline (chloroquine or primaquine) than a non-active quinoline platform; (iv) cations of ferrocenyl quinolines are highly convenient to generate water-soluble compounds with appropriate physicochemical properties; (v) the ferrocenyl quinolines promoted a specific mechanism based on oxidative stress-inducing morphological changes and early apoptosis and promoting immunostimulation in an infected animal model; (vi) a ferrocene–quinoline compound, compound 8, was identified as promising agent by its curative effect and parasitemia reduction in in vivo models of visceral leishmaniasis and by its excellent pharmacokinetic/pharmacodynamics and oral bioavailability. Further investigations of the metal-NHC-quinolines are needed to optimize the structures for lowering toxicity on the host cells, which compromises selectivity.
Considering the potential of the ferrocenyl motif-derived compounds to generate active and selective antileishmanial agents, metals and metalloids containing quinoline ferrocenyl derivatives are promising hit compounds for the development of new agents for the treatment of leishmaniasis. In addition, further preclinical investigations are needed to evaluate the potential of other promising compounds (e.g., [Ga(CH3)(L2-H)2], [Ga(CH3)2(L5-H)], and compounds 10, 14, and 34) as leishmanicidals. Collectively, the reported data underscore the need for further exploration of metal and metalloid quinoline derivatives as promising candidates in the development of novel antileishmanial agents.
Author contributions
EC: Conceptualization, Formal Analysis, Investigation, Methodology, Validation, Writing – original draft. LH: Investigation, Writing – original draft. VL: Investigation, Methodology, Writing – review and editing. FJ: Investigation, Writing – review and editing. HC: Data curation, Validation, Visualization, Writing – review and editing. GS: Data Curation, Validation, Writing – review and editing. DG: Conceptualization, Data Curation, Formal Analysis, Supervision, Validation, Writing – review and editing. AR: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by PEDECIBA (Programa de Desarrollo de las Ciencias Básicas) under Despegue-Científico 2023 funds as well as Comisión Sectorial de Investigación científica (CSIC) under project grant 22520220100622UD. HC, GS, DG, and AH thank to Sistema Nacional de Investigadores - Uruguay (SNI-Uruguay).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declare that no Generative AI was used in the creation of this manuscript.
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References
Aronson, N., Herwaldt, B. L., Libman, M., Pearson, R., Lopez-Velez, R., Weina, P., et al. (2016). Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the infectious diseases society of America (IDSA) and the American society of tropical medicine and hygiene (ASTMH). Clin. Inf. Dis. 63, 1539–1557. doi:10.1093/cid/ciw742
Avanzo, R. E., Garcia-Linares, G., Rodriguez, N., and Romero, A. H. (2025). A comprehensive revision on the use of quinoline antimalarial drugs as leishmanicidal agents. Front. Chem. 13. doi:10.3389/fchem.2025.1608340
Braga, S. (2022). Ruthenium complexes, an emerging class of leishmanicidal drug candidates. Appl. Biosci. 1, 129–142. doi:10.3390/applbiosci1020009
Chartlon, R. L., Rossi-Bergmann, B., Denny, P. W., and Steel, P. G. (2017). Repurposing as a strategy for the discovery of new anti-leishmanials: the-state-of-the-art. Parasitology 145, 219–236. doi:10.1017/s0031182017000993
Colotti, G., Ilari, A., Fiorillo, A., Baiocco, P., Cinellu, M. A., Maiore, L., et al. (2013). Metal-based compounds as prospective antileishmanial agents: inhibition of trypanothione reductase by selected gold complexes. ChemMedChem 8, 1634–1637. doi:10.1002/cmdc.201300276
Crans, D. C., and Kostenkova, K. (2020). Open questions on the biological roles of first-row transition metals. Comm. Chem. 3 (1), 104. doi:10.1038/s42004-020-00341-w
Del Carpio, E., Hernández, L., Ciangherotti, C., Villalobos Coa, V., Jiménez, L., Lubes, V., et al. (2018). Vanadium: history, chemistry, interactions with α-amino acids and potential therapeutic applications. Coord. Chem. Rev. 372, 117–140. doi:10.1016/j.ccr.2018.06.002
Delgado, F., Benítez, A., Gotopo, L., and Romero, A. (2025). 4-Aminoquinoline: a comprehensive review of synthetic strategies. Front. Chem. 13, doi:10.3389/fchem.2025.1553975
Drugs for Neglected Diseases initiative. (2023). Research-Development and portafolio. Available online at: https://www.dndi.org/research-development/portfolio. Accessed 28 April 2023.
Duffin, R. N., Blair, V. L., Kedzierski, L., and Andrews, P. C. (2017). Comparative stability, toxicity and anti-leishmanial activity of triphenyl antimony(v) and bismuth(v) α-hydroxy carboxylato complexes. Dalton Trans. 47 (3), 971–980. doi:10.1039/c7dt04171c
Duffin, R. N., Blair, V. L., Kędzierski, L., and Andrews, P. C. (2020). Alkyl gallium(III) quinolinolates: a new class of highly selective anti-leishmanial agents. Eur. J. Med. Chem. 186, 111895. doi:10.1016/j.ejmech.2019.111895
Duffin, R. N., Blair, V. L., Kedzierski, L., and Andrews, P. C. (2021). Development of new combination anti-leishmanial complexes: triphenyl Sb(v) mono-hydroxy mono-quinolinolates. J. Inorg. Biochem. 219, 111385. doi:10.1016/j.jinorgbio.2021.111385
Everson da Silva, L., Teixeira de Sousa, P., Nunes Maciel, E., Korting Nunes, R., Eger, I., Steindel, M., et al. (2010). In vitro antiprotozoal evaluation of zinc and copper complexes based on sulfonamides containing 8-aminoquinoline ligands. Lett. Drug Des. Discov. 7, 679–685. doi:10.2174/157018010792929586
Fiore-Apuzzo, C., Sullivan, E. S., Platt, D. C., Seger-Held, I., and Jones, M. A. (2021). Leishmania tarentolae novel responses to Bi3+-doped strontium aluminum oxyfluorides. Heliyon 7, e07896–96. doi:10.1016/j.heliyon.2021.e07896
Fricker, S. P., Mosi, R. M., Cameron, B. R., Baird, I., Zhu, Y., Anastassov, V., et al. (2008). Metal compounds for the treatment of parasitic diseases. J. Inorg. Biochem. 102, 1839–1845. doi:10.1016/j.jinorgbio.2008.05.010
Gambino, D. (2024). Organometallics in medicinal chemistry: antiparasitic agents. J. Braz. Chem. Soc. 35, 1–21. e-20240104. doi:10.21577/0103-5053.20240104
Gambino, D., and Otero, L. (2018). Design of prospective antiparasitic metal-based compounds including selected organometallic cores. Inorg. Chim. Acta 472, 58–75. doi:10.1016/j.ica.2017.07.068
Glans, L., Hu, W., Jöst, C., de Kock, C., Smith, P. J., Haukka, M., et al. (2012). Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, leishmaniasis, and trypanosomiasis. Dalton Trans. 41, 6443. doi:10.1039/C2DT30077J
Hemmert, C., Gornitzka, H., Deraeve, C., and Stiglian, J. L. (2025). Current state of the art of gold complexes as antileishmanial agents. Coord. Chem. Rev. 528, 216408. doi:10.1016/j.ccr.2024.216408
Hernández, L., Lorena Araujo, M., Madden, M., Del Carpio, E., Lubes, V., and Lubes, G. (2022). Vanadium complexes with polypyridyl ligands: speciation, structure and potential medicinal activity. J. Inorg. Biochem. 229, 111712. doi:10.1016/j.jinorgbio.2022.111712
Islam, A., Gomes-Da Silva, J., Moan-Berbet, F., Lages-Rodrigues, B., Beraldo, H., Melo, M. N., et al. (2014). Triphenylantimony(v) and triphenylbismuth(v) complexes with benzoic acid derivatives: structural characterization, in vitro antileishmanial and antibacterial activities and cytotoxicity against macrophages. Molecules 19, 6009–6030. doi:10.3390/molecules19056009
Jimenez-Falcao, S., and Mendez-Arriaga, J. M. (2024). Recent advances in metal complexes based on biomimetic and biocompatible organic ligands against leishmaniasis infections: state of the art and alternatives. Inorganics 12, 190. doi:10.3390/inorganics12070190
Karges, J., Stokes, R. W., and Cohen, S. M. (2021). Metal complexes for therapeutic applications. Trend. Chem. 3, 523–534. doi:10.1016/j.trechm.2021.03.006
Kondratskyi, A., Kondratska, K., Vanden Abeele, F., Gordienko, D., Dubois, C., Toillon, R. A., et al. (2017). Ferroquine, the next generation antimalarial drug, has antitumor activity. Sci. Rep. 7, 15896. article number. doi:10.1038/s41598-017-16154-2
Kostenkova, K., Scalese, G., Gambino, D., and Crans, D. C. (2022). Highlighting the roles of transition metals and speciation in chemical biology. Curr. Opin. Chem. Biol. 69, 102155–55. doi:10.1016/j.cbpa.2022.102155
Kumari, S., Kumar, V., Kumar-Tiwari, R., Ravidas, V., Pandey, K., and Kumar, A. (2022). Amphotericin B: a drug of choice for visceral leishmaniasis. Act. Trop. 235, 106661. doi:10.1016/j.actatropica.2022.106661
Mbaba, M., Khanye, S. D., Smith, G. S., and Biot, C. (2022). Organometallic chemistry of drugs based on iron. January: Elsevier EBooks, 261–296. doi:10.1016/b978-0-12-820206-7.00046-9
Medina-Franco, J. L., López-López, E., Andrade, E., Ruiz-Azuara, L., Frei, A., Guan, D., et al. (2022). Bridging informatics and medicinal inorganic chemistry: toward a database of metallodrugs and metallodrug candidates. Drug Discov. Today 27, 1420–1430. doi:10.1016/j.drudis.2022.02.021
Mendes, B., de Oliveira Cardoso, J. M., Fortes De Brito, R. C., Coura-Vital, W., de Oliveira Aguiar-Soares, R. D., and Barbosa Reis, A. (2020). Recent advances and new strategies on leishmaniasis treatment. Appl. Microbiol. Biotech. 104, 8965–8977. doi:10.1007/s00253-020-10856-w
Mota, S., Guedes, B. N., Jain, S., Cardoso, J. C., Severino, P., and Souto, E. B. (2024). Classical and innovative drugs for the treatment of Leishmania infections. Discov. Public Health 21 (1), 122. doi:10.1186/s12982-024-00247-1
Mukherjee, D., Yousuf, M., Dey, S., Chakraborty, S., Chaudhuri, A., Kumar, V., et al. (2020). Targeting the trypanothione reductase of tissue-ResidingLeishmaniain hosts’ reticuloendothelial system: a flexible water-soluble ferrocenylquinoline-based preclinical drug candidate. J. Med. Chem. 63, 15621–15638. doi:10.1021/acs.jmedchem.0c00690
Mukhopadhyay, R., Bisacchi, D., Zhou, Y., Armirotti, A., and Bordo, A. (2009). Structural characterization of the as/Sb reductase LmACR2 from Leishmania major. J. Mol. Biol. 386, 1229–1239. doi:10.1016/j.jmb.2008.07.056
Murray, H. W., Berman, J. D., Davies, C. R., and Saravia, N. G. (2005). Advances in leishmaniasis. Lancet 366 (9496), 1561–1577. doi:10.1016/s0140-6736(05)67629-5
Mushtaq, R., Khawar-Rauf, M., Bolte, M., Nadhman, A., Badshah, A., Tahir, M. N., et al. (2016). Synthesis, characterization and antileishmanial studies of some bioactive heteroleptic pentavalent antimonials. Appl. Organomet. Chem. 31, 5. doi:10.1002/aoc.3606
Navarro, M., and Visbal, G. (2015). Editors J. O. Nriagu,, and E. P. Skaar (PubMed. Cambridge (MA): MIT Press). Available online at: https://www.ncbi.nlm.nih.gov/books/NBK569689/.Metal-based antiparasitic therapeutics
Nih.gov (2022). Adverse effects of antileishmanial medicines. Available online at: https://www.ncbi.nlm.nih.gov/books/NBK581524/(Accessed November 19, 2024).
Ong, Y. C., Roy, S., Andrews, P. C., and Gasser, G. (2018). Metal compounds against neglected tropical diseases. Chem. Rev. 119, 730–796. doi:10.1021/acs.chemrev.8b00338
Ouellette, M., Drummelsmith, J., and Papadopoulou, B. (2004). Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resist. Updat. 7, 257–266. doi:10.1016/j.drup.2004.07.002
Paloque, L., Hemmert, C., Valentin, A., and Gornitzka, H. (2015). Synthesis, characterization, and antileishmanial activities of gold(I) complexes involving quinoline functionalized N-heterocyclic carbenes. Eur. J. Med. Chem. 94, 22–29. doi:10.1016/j.ejmech.2015.02.046
Pomel, S., Biot, C., Bories, C., and Loiseau, P. M. (2012). Antiprotozoal activity of ferroquine. Parasitol. Res. 112, 665–669. doi:10.1007/s00436-012-3183-4
Pomel, S., Dubar, F., Forge, D., Loiseau, P. M., and Biot, C. (2015). New heterocyclic compounds: synthesis and antitrypanosomal properties. Bioorg. Med. Chem. 23, 5168–5174. doi:10.1016/j.bmc.2015.03.029
Quintal, S., Morais, T. S., Matos, C. P., Robalo, M. P., Piedade, M., Villa, M. J., et al. (2013). Synthesis, structural characterization and leishmanicidal activity evaluation of ferrocenyl N-heterocyclic compounds. J. Organomet. Chem. 745-746, 299–311. doi:10.1016/j.jorganchem.2013.07.044
Rivas, F., Del Mármol, C., Scalese, G., Pérez-Díaz, L., Machado, I., Blacque, O., et al. (2022). New multifunctional Ru (II) organometallic compounds show activity against Trypanosoma brucei and Leishmania infantum. J. Inorg. Biochem. 237, 112016. doi:10.1016/j.jinorgbio.2022.112016
Romero, A., and Delgado, F. (2024). 4-Aminoquinoline as a privileged scaffold for the design of leishmanicidal agents: structure–property relationships and key biological targets. Front. Chem. 12, 1527946. doi:10.3389/fchem.2024.1527946
Romero, A., Rodriguez, N., Lopez, S. E., and Oviedo, H. (2019). Identification of dehydroxy isoquine and isotebuquine as promising antileishmanial agents. Arch. Pharm. 352 (5), 1800281. doi:10.1002/ardp.201800281
Rosa, L. B., Aires, R. L., liveira, L. S., ontes, J. V., Miguel, D. C., and Abbehausen, C. (2021). A “Golden Age” for the discovery of new antileishmanial agents: current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system. ChemMedChem. 16, 1681–1695. doi:10.1002/cmdc.202100022
Scalese, G., Machado, I., Correia, I., Costa-Pessoa, J., Bilbao, L., Pérez-Diaz, L., et al. (2019). Exploring oxidovanadium(iv) homoleptic complexes with 8-hydroxyquinoline derivatives as prospective antitrypanosomal agents. New J. Chem. 43, 17756–17773. doi:10.1039/c9nj02589h
Scalese, G., Machado, I., Salazar, F., Coitiño, E. L., Correia, I., Pessoa, J. C., et al. (2024a). Facing diseases caused by trypanosomatid parasites: rational design of multifunctional oxidovanadium (IV) complexes with bioactive ligands. Front. Chem. Biol. 2, 1304571. doi:10.3389/fchbi.2023.1304571
Scalese, G., Mosquillo, M. F., Pérez-Díaz, L., and Gambino, D. (2024b). Biosynthesis of ergosterol as a relevant molecular target of metal-based antiparasitic and antifungal compounds. Coord. Chem. Rev. 503, 215608. doi:10.1016/j.ccr.2023.215608
Silva, C. F. M., Leão, T., Dias, F., Tomás, A. M., Pinto, D. C. G. A., Oliveira, E. F. T., et al. (2023). Structure-activity relationship studies of 9-alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum promastigotes. Pharmaceutics 15, 669. doi:10.3390/pharmaceutics15020669
Sundar, S., Singh, J., Kumar-Singh, K., Agrawal, N., and Kumar, R. (2024). Current and emerging therapies for the treatment of leishmaniasis. Exp. Opin. Orphan Drugs 12, 19–32. doi:10.1080/21678707.2024.2335248
Tahghighi, A. (2014). Importance of metal complexes for development of potential leishmanicidal agents. J. Organomet. Chem. 770, 51–60. doi:10.1016/j.jorganchem.2014.08.007
Vale-Costa, S., Costa-Gouveia, J., Pérez, B., Silva, T., Teixeira, C., Gomes, P., et al. (2013). N-cinnamoylated aminoquinolines as promising antileishmanial agents. Antimicr. Agent. Chemother. 57, 5112–5115. doi:10.1128/aac.00557-13
Vale-Costa, S., Vale, N., Matos, J., Tomás, A., Moreira, R., Gomes, P., et al. (2012). Peptidomimetic and organometallic derivatives of primaquine active against Leishmania infantum. Antimicr. Agents Chemother. 56, 5774–5781. doi:10.1128/aac.00873-12
Van Staveren, D. R., and Metzler-Nolte, N. (2004). Bioorganometallic chemistry of ferrocene. Chem. Rev. 104, 5931–5986. doi:10.1021/cr0101510
World Health Organization (2023). “Leishmaniasis.” World Health organization. World Health Organization: WHO. Available online at: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis January 12, 2023.
Yaluff, G., Herrera, L. M., Rolon, M., Vega, C., and Cerecetto, H. (2025). The quinoline framework and related scaffolds in natural products with anti-Leishmania properties. Front. Chem. 13, 1571067. doi:10.3389/fchem.2025.1571067
Yousuf, M., Mukherjee, D., Dey, S., Pal, C., and Adhikari, S. (2016). Antileishmanial ferrocenylquinoline derivatives: synthesis and biological evaluation against Leishmania donovani. Eur. J. Med. Chem. 124, 468–479. doi:10.1016/j.ejmech.2016.08.049
Yousuf, M., Mukherjee, D., Pal, A., Dey, S., Mandal, S., Pal, C., et al. (2015). Synthesis and biological evaluation of ferrocenylquinoline as a potential antileishmanial agent. ChemMedChem 10, 546–554. doi:10.1002/cmdc.201402537
Keywords: quinoline, Leishmania, ferrocene, N-heterocyclic carbenes, 8-quinolinate
Citation: Del Carpio E, Hernández L, Lubes V, Jourdan F, Cerecetto H, Scalese G, Gambino D and Romero AH (2025) Current developments of metal- and metalloid-based quinoline compounds as leishmanicidal agents. Front. Chem. 13:1586044. doi: 10.3389/fchem.2025.1586044
Received: 01 March 2025; Accepted: 01 May 2025;
Published: 30 May 2025.
Edited by:
Andrea Erxleben, University of Galway, IrelandReviewed by:
Subhash Chander, Amity University, IndiaCopyright © 2025 Del Carpio, Hernández, Lubes, Jourdan, Cerecetto, Scalese, Gambino and Romero. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Edgar Del Carpio, ZWRnYXJkZWxjYXJwaW9AZ21haWwuY29t; Dinorah Gambino, ZGdhbWJpbm9AZnEuZWR1LnV5; Angel H. Romero, YW5nZWwudWN2LnVzYkBnbWFpbC5jb20=
†ORCID: Edgar Del Carpio, orcid.org/0000-0001-7358-6178; Lino Hernández, orcid.org/0000-0003-3978-6269; Vito Lubes, orcid.org/0000-0003-0966-3428; Hugo Cerecetto, orcid.org/0000-0003-1256-3786; Gonzalo Scalese, orcid.org/0000-0002-5386-6225; Dinorah Gambino, orcid.org/0000-0001-8678-7374; Angel H. Romero, orcid.org/0000-0001-8747-5153