Inhibition of <i>Toxoplasma gondii</i> by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine

Węglińska, Lidia; Bekier, Adrian; Trotsko, Nazar; Kaproń, Barbara; Plech, Tomasz; Dzitko, Katarzyna; Paneth, Agata

doi:10.1080/14756366.2022.2112576

Cited by 8 publications

(5 citation statements)

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“…Control of T. gondii is a major challenge since the parasite can cross the blood–brain barrier to develop a persistent infection where most chemicals are inaccessible [ 31 ]. Currently, the combination of pyrimethamine and sulfadiazine is commonly used clinically for the treatment of acute toxoplasmosis [ 32 ]. However, these drugs have limited effects on T. gondii cysts.…”

Section: Discussionmentioning

confidence: 99%

A live attenuated RHΔompdcΔuprt mutant of Toxoplasma gondii induces strong protective immunity against toxoplasmosis in mice and cats

et al. 2023

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Background Toxoplasma gondii is an obligate intracellular apicomplexan parasite and is responsible for zoonotic toxoplasmosis. It is essential to develop an effective anti-T. gondii vaccine for the control of toxoplasmosis, and this study is to explore the immunoprotective effects of a live attenuated vaccine in mice and cats. Methods First, the ompdc and uprt genes of T. gondii were deleted through the CRISPR-Cas9 system. Then, the intracellular proliferation and virulence of this mutant strain were evaluated. Subsequently, the immune responses induced by this mutant in mice and cats were detected, including antibody titers, cytokine levels, and subsets of T lymphocytes. Finally, the immunoprotective effects were evaluated by challenge with tachyzoites of different strains in mice or cysts of the ME49 strain in cats. Furthermore, to discover the effective immune element against toxoplasmosis, passive immunizations were carried out. GraphPad Prism software was used to conduct the log-rank (Mantel–Cox) test, Student’s t test and one-way ANOVA. Results The RHΔompdcΔuprt were constructed by the CRISPR-Cas9 system. Compared with the wild-type strain, the mutant notably reduced proliferation (P < 0.05). In addition, the mutant exhibited virulence attenuation in both murine (BALB/c and BALB/c-nu) and cat models. Notably, limited pathological changes were found in tissues from RHΔompdcΔuprt-injected mice. Furthermore, compared with nonimmunized group, high levels of IgG (IgG1 and IgG2a) antibodies and cytokines (IFN-γ, IL-4, IL-10, IL-2 and IL-12) in mice were detected by the mutant (P < 0.05). Remarkably, all RHΔompdcΔuprt-vaccinated mice survived a lethal challenge with RHΔku80 and ME49 and WH6 strains. The immunized sera and splenocytes, especially CD8+ T cells, could significantly extend (P < 0.05) the survival time of mice challenged with the RHΔku80 strain compared with naïve mice. In addition, compared with nonimmunized cats, cats immunized with the mutant produced high levels of antibodies and cytokines (P < 0.05), and notably decreased the shedding numbers of oocysts in feces (95.3%). Conclusions The avirulent RHΔompdcΔuprt strain can provide strong anti-T. gondii immune responses, and is a promising candidate for developing a safe and effective live attenuated vaccine. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

A live attenuated RHΔompdcΔuprt mutant of Toxoplasma gondii induces strong protective immunity against toxoplasmosis in mice and cats

et al. 2023

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“…The 1,2,4-triazole derivative (69) (4-(3,4-dimethoxyphenyl)-5-(4methylimidazol-5-yl) triazole-1,2,4-thione-3) shows an exciting lead structure in the hunt for new anti-Toxoplasma medications. [73] Pathak et al S. aureus that was comparable to that of the standard ciprofloxacin.…”

Section: As An Anticancer Agent: 124-triazole Derivativesmentioning

confidence: 98%

“…In addition, it did not significantly alter red blood cells′ (RBCs′) hemolytic properties. The 1,2,4‐triazole derivative (69) (4‐(3,4‐dimethoxyphenyl)‐5‐(4‐methylimidazol‐5‐yl) triazole‐1,2,4‐thione‐3) shows an exciting lead structure in the hunt for new anti‐Toxoplasma medications [73] …”

Section: Novel Advancements In 124‐triazole Derivatives For Biologica...mentioning

confidence: 99%

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity

Ajmal,

Mahato,

Khan

et al. 2024

Chemistry & Biodiversity

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One of the triazole tautomers, 1,2,4‐triazole derivatives, has a wide range of biological activities that suggest its potential therapeutic utility in medicinal chemistry. These actions include anti‐inflammatory, anti‐cancer, anti‐bacterial, anti‐tuberculosis, and anti‐diabetic effects. The review highlights anti‐inflammatory effect of 1,2,4‐triazoles in relation to their ability to disrupt significant inflammatory mediators and pathways. We present in‐silico data that illuminate the triazoles capacity to inhibit cell division, encourage apoptosis, and stop metastasis in a range of cancer models. This review looks at the bactericidal and bacteriostatic properties of 1,2,4‐triazole derivatives, with a focus on their potential efficacy against multi‐drug resistant bacterial infections and their usage in tuberculosis therapy. In order to better understand these substances' potential anti‐diabetic benefits, this review also looks at how they affect glucose metabolism regulation and insulin responsiveness. Based on information provided, it can be concluded that 1,2,4‐triazole derivatives are a promising class of diverse therapeutic agents with potential utility in a range of disorders. Their development and improvement might herald a new era of medical care that will be immensely advantageous to both patients and medical community as a whole. Additionally, this study encourages more research into these substances and their enhancement for use in pharmaceutical development.

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“…CRL-1807), were cultured in RPMI 1640 + dulbecco's modified eagle medium (DMEM) (1:1) medium (Sigma, St. Louis, MO), supplemented with 10% FCS and antibiotics, at 34 • C in a 5% CO 2 /95% air atmosphere [78]. Human glioblastoma T98G cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Sigma Aldrich, St. Louis, MO, USA), supplemented with 10% fetal bovine serum (FBS), penicillin (100 U/mL), and streptomycin (100 µg/mL) [79]. Human hepatocellular carcinoma cells, HepG2, were maintained in Eagle's Minimum Essential Medium, supplemented with 10% FBS, penicillin (100 U/mL), and streptomycin (100 µg/mL) [44].…”

Section: Cell Culturesmentioning

confidence: 99%

Combined In Silico and In Vitro Analyses to Assess the Anticancer Potential of Thiazolidinedione–Thiosemicarbazone Hybrid Molecules

Paneth,

Kaproń,

Plech

et al. 2023

IJMS

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The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future leading causes of death globally. To address this issue, based on a combined in silico and in vitro approach, we explored the anticancer potential of known antibacterials with a thiazolidinedione–thiosemicarbazone (TZD–TSC) core structure. A cytotoxicity assessment showed encouraging results for compounds 2–4, with IC50 values against T98G and HepG2 cells in the low micromolar range. TZD–TSC 3 proved to be most toxic to cancer cell lines, with IC50 values of 2.97 ± 0.39 µM against human hepatoma HepG2 cells and IC50 values of 28.34 ± 2.21 µM against human glioblastoma T98G cells. Additionally, compound 3 induced apoptosis and showed no specific hemolytic activity. Furthermore, treatment using 3 on cancer cell lines alters these cells’ morphology and further suppresses migratory activity. Molecular docking, in turn, suggests that 3 would have the capacity to simultaneously target HDACs and PPARγ, by the activation of PPARγ and the inhibition of both HDAC4 and HDAC8. Thus, the promising preliminary results obtained with TZD–TSC 3 represent an encouraging starting point for the rational design of novel chemotherapeutics with dual antibacterial and anticancer activities.

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Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine

Cited by 8 publications

References 70 publications

A live attenuated RHΔompdcΔuprt mutant of Toxoplasma gondii induces strong protective immunity against toxoplasmosis in mice and cats

A live attenuated RHΔompdcΔuprt mutant of Toxoplasma gondii induces strong protective immunity against toxoplasmosis in mice and cats

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity

Combined In Silico and In Vitro Analyses to Assess the Anticancer Potential of Thiazolidinedione–Thiosemicarbazone Hybrid Molecules

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