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Synthesis and anti-Toxoplasma activity of indole-triazole compounds on tachyzoites of RH strain.

ABSTRACT:

Background

Conventional treatment for toxoplasmosis have severe side effects and the inability to completely eradicate the disease. Therefore, the acquisition of new anti-Toxoplasma drugs has always been of interest among researchers. In the present study, we prepare a new indole-triazole derivatives and evaluated their potential anti-parasitic activity against tachyzoites of Toxoplasma RH strain.

Materials and methods

In this study, after synthesis of the two new compounds of indole-triazole, the effect of their different concentrations (2-1024 μg/ml) were determined on Toxoplasma tachyzoites using flow cytometry. Furthermore, tachyzoites were exposed to different concentrations of compounds (4, 16, 64, 265, 1024 μg/ml) for 1.5 h and their infectivity were evaluated in BALB/c mice.

Results

The flow cytometry results indicated the benzyl derivative of indole-triazole in various concentrations had a lethal effect on tachyzoites between 11.93% and 89.66%, while the naphthalene derivative had a lethality of 26.63%-66.82%. The infectivity analysis showed that the survival time of mice at concentrations of 1024 μg/ml and 512 μg/ml of benzyl derivatives was significantly increased (P = 0.008 and P = 0.016, respectively), compared to that in the negative control group. Furthermore, survival time of mice was statistically significant at the concentration of 1024 μg/ml for naphthyl derivative (P = 0.012).

Conclusion

Findings of the current study suggested indole triazole compounds, based on their structure and enzymes targeting, have a considerable effect on tachyzoites of T. gondii RH strain and can be considered as a new anti-Toxoplasma agent.

SUBMITTER: Bahreini MS

PROVIDER: S-EPMC8777237 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Toxoplasma gondii is a globally distributed obligate intracellular parasite which can cause zoonotic toxoplasmosis with great harms. The average death time of mice that infected with Toxoplasma gondii RH strain tachyzoites recovered from the liquid nitrogen was shortened after multiple generations. It has been reported that the parasite is in a state of static virulence during cryopreservation and the virulence of the protozoan parasite can be enhanced after continuous passages in hosts under laboratory conditions. However, no research has been conducted to elucidate its biological mechanism. Herein, we sequenced the T. gondii transcriptome using RNA-Seq technology and performed de novo assembly to investigated the virulence factors expression changes by comparing gene expression profiles between incipiently recovered and completely resuscitated tachyzoites. Transcriptome analysis identified 1,951 differentially expressed transcripts in infected liver, of which 1,752 were significantly downregulated and 199 upregulated. We identified many differentially expressed proteins and genes, including serine/threonine kinase, calnexin, myosin and microtubule-associated protein which have previously been reported to be either involved in cell adhesion, parasite gliding or participate in cell invasion. The great majority of the virulence factors including microneme proteins, rhoptry proteins and dense granule proteins were upregulated in fully recovered tachyzoites. The enhanced virulence of recovered Toxoplasma gondii RH strain from the liquid nitrogen is associated with the up-regulated expression of MICs, ROPs and GRAs. Our data will facilitate future genomic research and in-depth annotation of Toxoplasma gondii RH strain genomes. This study provides a profile of the candidate genes that are suspected to be involved with virulence enhancement of recovered Toxoplasma gondii RH strain tachyzoites. Many further studies should be carried out to confirm the function of the candidate genes. Moreover, the preliminary identification of genes and pathways exhibiting differential expression in complete resuscitation stage may further our general understanding of virulence enhancement in this parasite.