In vitro and in vivo activities of a trithiolato-diRuthenium complex conjugated with sulfadoxine against the apicomplexan parasite Toxoplasma gondii.

Boubaker, Ghalia; Bernal, Alice; Vigneswaran, Anitha; Imhof, Dennis; Ferreira de Sousa, Maria Cristina; Hänggeli, Kai Pascal Alexander; Haudenschild, Noé; Furrer, Julien; Păunescu, Emilia; Desiatkina, Oksana; Hemphill, Andrew (2024). In vitro and in vivo activities of a trithiolato-diRuthenium complex conjugated with sulfadoxine against the apicomplexan parasite Toxoplasma gondii. International journal for parasitology. Drugs and drug resistance, 25(100544), p. 100544. Elsevier 10.1016/j.ijpddr.2024.100544

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Organometallic compounds, including Ruthenium complexes, have been widely developed as anti-cancer chemotherapeutics, but have also attracted much interest as potential anti-parasitic drugs. Recently hybrid drugs composed of organometallic Ruthenium moieties that were complexed to different antimicrobial agents were synthesized. One of these compounds, a trithiolato-diRuthenium complex (RU) conjugated to sulfadoxine (SDX), inhibited proliferation of Toxoplasma gondii tachyzoites grown in human foreskin fibroblast (HFF) monolayers with an IC50 < 150 nM, while SDX and the non-modified RU complex applied either individually or as an equimolar mixture were much less potent. In addition, conjugation of SDX to RU lead to decreased HFF cytotoxicity. RU-SDX did not impair the in vitro proliferation of murine splenocytes at concentrations ranging from 0.1 to 0.5 μM but had an impact at 2 μM, and induced zebrafish embryotoxicity at 20 μM, but not at 2 or 0.2 μM. RU-SDX acted parasitostatic but not parasiticidal, and induced transient ultrastructural changes in the mitochondrial matrix of tachyzoites early during treatment. While other compounds that target the mitochondrion such as the uncouplers FCCP and CCCP and another trithiolato-Ruthenium complex conjugated to adenine affected the mitochondrial membrane potential, no such effect was detected for RU-SDX. Evaluation of the in vivo efficacy of RU-SDX in a murine T. gondii oocyst infection model comprised of non-pregnant outbred CD1 mice showed no effects on the cerebral parasite burden, but reduced parasite load in the eyes and in heart tissue.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Boubaker, Ghalia, Bernal, Alice Jeanine Felisa, Vigneswaran, Anitha, Imhof, Dennis, Ferreira de Sousa, Maria Cristina, Hänggeli, Kai Pascal Alexander, Haudenschild, Noé Marc, Furrer, Julien, Paunescu, Emilia, Desiatkina, Oksana, Hemphill, Andrew

Subjects:

600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry
000 Computer science, knowledge & systems

ISSN:

2211-3207

Publisher:

Elsevier

Language:

English

Submitter:

Pubmed Import

Date Deposited:

06 May 2024 14:23

Last Modified:

10 Aug 2024 00:13

Publisher DOI:

10.1016/j.ijpddr.2024.100544

PubMed ID:

38703737

Uncontrolled Keywords:

Cytotoxicity In vivo efficacy Organometallic drugs Proliferation inhibition Splenocytes Sulfadoxine Toxoplasma Transmission electron microscopy Trithiolato diruthenium complex

BORIS DOI:

10.48350/196531

URI:

https://boris.unibe.ch/id/eprint/196531

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