Potent anti-Toxoplasma gondii activity of 4-chlorophenylthioacetone-derived thiosemicarbazones: Involvement of CCR2 and CCR5 receptors and 5-lipoxygenase in the mode of action

• Published in: Medicine in drug discovery Vol. 18; p. 100157
• Main Authors: Nonato Rabelo, Rayane Aparecida, Rodrigues de Assis, Diego Rodney, Almeida Oliveira, Alexandre, Nascimento Barbosa, César Luís, das Dores Pereira, Rafaela, Wagner de Almeida Vitor, Ricardo, Bento Régis, Wiliam César, Martins Teixeira, Mauro, Beraldo, Heloísa, Simão Machado, Fabiana
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-06-2023; Elsevier
• Subjects: Immune response; Macrophages; Thiosemicarbazones; Toxoplasma gondii; Toxoplasmose; NO; Immune response; 5-LO; KO; CNS; I.P; Toxoplasmose; Macrophages; TNF; MOs; LDH; IFN-γ; Toxoplasma gondii; Tg; Thiosemicarbazones; ROS; CCR5; DPI; LXAs; WT; CCR2
• ISSN: 2590-0986; 2590-0986
• DOI: 10.1016/j.medidd.2023.100157

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•Thiosemicarbazones Ca and Cb represent potent anti-Toxoplasma drug candidates.•Ca and Cb attenuate Toxoplasma gondii (Tg) growth in macrophages and glial cells.•Compounds control Tg replication acting on the parasite in infected host cells.•Ca and Cb possess potent anti-Toxoplasma activity in vitro and in vivo.•Compounds increase cytokine production and raise the survival rate of Tg-infected mice.
Toxoplasmosis is a disease requiring therapeutic innovation, and thiosemicarbazones with antimicrobial activity are candidates to control Toxoplasma gondii infection. Here, the anti-T. gondii activities of (E)-2-(1-(4-chlorophenylthio)propan-2-ylidene)-hydrazinecarbothioamides (Ca and Cb) were investigated. T. gondii-infected macrophages (MOs) or glial cells treated with Ca or Cb showed a decrease in the number of intracellular parasites. A deficiency in the chemokine receptor CCR2, but not CCR5, partially reduced anti-T. gondii activity induced by Ca or Cb. In contrast, a deficiency in 5-lipoxygenase (5-LO) activity potentiated anti-T. gondii activities induced by these compounds. In vivo treatment with Ca increased the survival of T. gondii-infected wild-type mice, and this was associated with increased IFN-γ and IL-12 production. A deficiency in CCR5 or CCR2 abolished the protective effect of Ca treatment in vivo, while a deficiency in 5-LO increased Cb anti-T. gondii effects. Collectively, our data suggest that Ca and Cb are potential therapeutic candidates for the treatment of toxoplasmosis.