The quest of the best – A SAR study of trithiolato-bridged dinuclear Ruthenium(II)-Arene compounds presenting antiparasitic properties

Păunescu, Emilia; Boubaker, Ghalia; Desiatkina, Oksana; Anghel, Nicoleta; Amdouni, Yosra; Hemphill, Andrew; Furrer, Julien

doi:10.1016/j.ejmech.2021.113610

Cited by 22 publications

(56 citation statements)

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“…Single-cell suspension from mouse spleen was prepared exactly as previously described [ 24 , 25 ]. Briefly, spleens of three 14-week-old female BALB/c mice were aseptically removed, minced, and passed through 40 µm cell strainers.…”

Section: Methodsmentioning

confidence: 99%

“…Alamar Blue assay on splenocytes was carried out as described previously [ 24 , 25 ]. Briefly, after 48 h of incubation at 37 °C in the presence of 5% CO 2 , 0.02 mL of a resazurin solution (0.1 mg/mL) was added to each well and fluorescence was measured at 0 and 5 h. Results represent the mean fluorescence of five replicates ± standard deviation.…”

Section: Methodsmentioning

confidence: 99%

“…The 5-bromo-2′-deoxyuridine (BrdU) cell proliferations assay was performed as described previously [ 24 , 25 ]. Shortly, BrdU was added to splenocytes cultures 18 h before the end of the experiment, and incorporation of BrdU was measured using BrdU cell proliferation kit (QIA58, Merck Millipore).…”

Section: Methodsmentioning

confidence: 99%

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Maca against Echinococcosis?—A Reverse Approach from Patient to In Vitro Testing

et al. 2021

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Drug-based treatment of alveolar echinococcosis (AE) with benzimidazoles is in most cases non-curative, thus has to be taken lifelong. Here, we report on a 56-year-old male AE patient who received standard benzimidazole treatment and biliary plastic stents, and additionally self-medicated himself with the Peruvian plant extract Maca (Lepidium meyenii). After 42 months, viable parasite tissue had disappeared. Based on this striking observation, the anti-echinococcal activity of Maca was investigated in vitro and in mice experimentally infected with Echinococcus multilocularis metacestodes. Albendazole (ABZ)-treated mice and mice treated with an ABZ+Maca combination exhibited a significantly reduced parasite burden compared to untreated or Maca-treated mice. As shown by a newly established UHPLC-MS/MS-based measurement of ABZ-metabolites, the presence of Maca during the treatment did not alter ABZ plasma levels. In vitro assays corroborated these findings, as exposure to Maca had no notable effect on E. multilocularis metacestodes, and in cultures of germinal layer cells, possibly unspecific, cytotoxic effects of Maca were observed. However, in the combined treatments, Maca inhibited the activity of ABZ in vitro. While Maca had no direct anti-parasitic activity, it induced in vitro proliferation of murine spleen cells, suggesting that immunomodulatory properties could have contributed to the curative effect seen in the patient.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Maca against Echinococcosis?—A Reverse Approach from Patient to In Vitro Testing

et al. 2021

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“…To access the hybrid molecules, selected diruthenium intermediates bearing functional groups enabling covalent tethering (i.e., via ester conjugation or click chemistry) of appropriately substituted compounds, were synthesized. The mixed trithiolato-bridged ruthenium(II)-arene intermediates 2 99 , 3 99 and 4 114 , functionalized with an amino, carboxy or hydroxy group respectively, were obtained following a twostep pathway (Scheme 1) using formerly reported procedures 99,114 . Precursor 1, obtained from the ruthenium dimer ([Ru(η 6 -p-MeC6H4Pr i )Cl2]2) and (4-(tert-butyl)phenyl)methanethiol 99 , was reacted (dimethylamino)pyridine) as basic catalyst and was isolated in 60% yield.…”

Section: Synthesis Of the Trithiolato-bridged Dinuclear Ruthenium(ii)...mentioning

confidence: 99%

New Nucleic Base-tethered Trithiolato-bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

Desiatkina

Mösching

Anghel

et al. 2022

Preprint

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Aiming to generate novel compounds with improved antitoxoplama activity by exploiting the parasite auxotrophies, a library of nucleic base-tethered trithiolato-bridged dinuclear ruthenium(II)-arene conjugates - was synthesized and evaluated. Various structural features as the nucleobase (adenine, uracil, cytosine, thymine, and xanthine) and the linker between the two units were progressively modified. To substantiate the concept, hybrid molecules comprising the diruthenium moiety and other type of pendant molecules were also synthesized and assessed. The use of the CuAAC (copper catalyzed azide-alkyne cycloaddition) approach for the obtainment of conjugates bearing the trithiolato diruthenium scaffold was validated. 37 Compounds (diruthenium conjugates and corresponding intermediates) were assessed in a primary screening for in vitro activity against transgenic Toxoplasma gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 μM. In parallel the cytotoxicity in non-infected host cells (human foreskin fibroblasts, HFF) was determined by alamarBlue assay. 20 Compounds strongly impairing parasite proliferation with little effect on HFF viability were subjected to T. gondii β-gal dose-response studies (IC50, half maximal inhibitory concentration determination) and their toxicity for HFF was assessed at 2.5 μM. Two compounds showing promise for further development were identified: 14, ester conjugate with 9-(2-oxyethyl)adenine, and 36, a click conjugate bearing a 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl substituent, with IC50 values of 0.059 and 0.111 μM respectively, significantly lower compared to the standard drug pyrimethamine (IC50 = 0.326 μM). Both 14 and 36 exhibited low toxicity against HFF when applied at 2.5 μM and are candidates as potential treatment options in a suitable in vivo model.

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“…In the last decades, the development of metal-based drugs has proven to be a promising approach in the search for new therapeutic tools against parasitic diseases. As a result of the research performed by several academic groups, a great number of classical coordination compounds and organometallics bearing antiparasitic activity were developed (Sánchez-Delgado et al, 2004;Navarro, 2009;Navarro et al, 2010;Gambino, 2011;Gambino and Otero, 2012;Salas et al, 2013;Tahghighi, 2014;Brown and Hyland, 2015;Pessoa et al, 2015;Camarada et al, 2016;Gambino and Otero, 2018;Marcelino et al, 2018;Ravera et al, 2018;Gambino and Otero, 2019;Markwalter et al, 2019;Ong et al, 2019;Mbaba et al, 2020;Păunescu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

Gambino

Otero

2022

Front. Chem.

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Human African Trypanosomiasis (HAT), Chagas disease or American Trypanosomiasis (CD), and leishmaniases are protozoan infections produced by trypanosomatid parasites belonging to the kinetoplastid order and they constitute an urgent global health problem. In fact, there is an urgent need of more efficient and less toxic chemotherapy for these diseases. Medicinal inorganic chemistry currently offers an attractive option for the rational design of new drugs and, in particular, antiparasitic ones. In this sense, one of the main strategies for the design of metal-based antiparasitic compounds has been the coordination of an organic ligand with known or potential biological activity, to a metal centre or an organometallic core. Classical metal coordination complexes or organometallic compounds could be designed as multifunctional agents joining, in a single molecule, different chemical species that could affect different parasitic targets. This review is focused on the rational design of palladium(II) and platinum(II) compounds with bioactive ligands as prospective drugs against trypanosomatid parasites that has been conducted by our group during the last 20 years.

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The quest of the best – A SAR study of trithiolato-bridged dinuclear Ruthenium(II)-Arene compounds presenting antiparasitic properties

Cited by 22 publications

References 86 publications

Maca against Echinococcosis?—A Reverse Approach from Patient to In Vitro Testing

Maca against Echinococcosis?—A Reverse Approach from Patient to In Vitro Testing

New Nucleic Base-tethered Trithiolato-bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

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