1,4-Disubstituted thiosemicarbazide derivatives are potent inhibitors of Toxoplasma gondii proliferation.

Katarzyna Dzitko,Agata Paneth,Piotr Paneth,Jakub Pawełczyk,Joanna Stefańska,Paweł Stączek,Tomasz Plech

doi:10.3390/molecules19079926

Abstract

A series of 4-arylthiosemicarbazides substituted at the N1 position with a 5-membered heteroaryl ring was synthesized and evaluated in vitro for T. gondii inhibition proliferation and host cell cytotoxicity. At non-toxic concentrations for the host cells all studied compounds displayed excellent anti-parasitic effects when compared to sulfadiazine, indicating a high selectivity of their anti-T. gondii activity. The differences in bioactivity investigated by DFT calculations suggest that the inhibitory activity of 4-aryl-thiosemicarbazides towards T. gondii proliferation is connected with the electronic structure of the molecule. Further, these compounds were tested as potential antibacterial agents. No growth-inhibiting effect on any of the test microorganisms was observed for all the compounds, even at high concentrations.

Highlights

Toxoplasma gondii (T. gondii) is a worldwide distributed protozoan responsible for toxoplasmosis, one of the most prevalent parasitic infections in humans [1,2]
We present the outcomes of these investigations, as well as the results of subsequent DFT calculations, which allowed us to suggest that inhibitory activity of 4-arylthiosemicarbazides towards T. gondii proliferation is connected with the electronic structure of the molecule
According to the structure-activity relationships (SAR) analysis results, the electronic nature of the substituents on the phenyl ring of the 4-aryl-1-(4methyl-1H-imidazole-5-yl)carbonylthiosemicarbazides seemed to have a low influence on bioactivity, indicating the dominant role of the imidazole moiety for modulating the bioactivity of the studied compounds

Summary

Introduction

Toxoplasma gondii (T. gondii) is a worldwide distributed protozoan responsible for toxoplasmosis, one of the most prevalent parasitic infections in humans [1,2]. T. gondii infection in immunocompetent hosts is minor, self-limiting, and the parasite becomes dormant. It can have serious effects on immunocompromised individuals, such as HIV-AIDS positive, cancer or organ transplant human patients [2,3]. Under such conditions, T. gondii can result in life-threatening toxoplasmosis with Toxoplasma encephalitis and other complications (i.a. necrotic lesions within the central nervous system or retinochoroiditis) [4,5]. Congenital T. gondii infection may result in serious neurological and ophthalmic damage to the fetus or even, especially in the first three months of the pregnancy, spontaneous abortion. Reactivation of undiagnosed congenital toxoplasmosis can lead to ocular toxoplasmosis later in life, in many cases causing blindness [6,7,8]

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Conclusion