Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

McFarland, Madalyn M.; Zach, Sydney J.; Wang, Xiaofang; Potluri, Lakshmi-Prasad; Neville, Andrew J.; Vennerstrom, Jonathan L.; Davis, Paul H.

doi:10.1128/aac.01176-16

Cited by 37 publications

(26 citation statements)

References 199 publications

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“…Here we discuss studies on anti-T. gondii drugs performed in humans and in animal models. For studies performed using in vitro models and screening approaches for new drugs, the reader is referred to recent expert reviews by Alday and Doggett (7), McFarland et al (8), Jin et al (9), Kortagere (10), Montazeri et al (11), and Sharif et al (12).…”

Section: Introductionmentioning

confidence: 99%

Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice

et al. 2018

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SUMMARYPrimary infection is usually subclinical, but cervical lymphadenopathy or ocular disease can be present in some patients. Active infection is characterized by tachyzoites, while tissue cysts characterize latent disease. Infection in the fetus and in immunocompromised patients can cause devastating disease. The combination of pyrimethamine and sulfadiazine (pyr-sulf), targeting the active stage of the infection, is the current gold standard for treating toxoplasmosis, but failure rates remain significant. Although other regimens are available, including pyrimethamine in combination with clindamycin, atovaquone, clarithromycin, or azithromycin or monotherapy with trimethoprim-sulfamethoxazole (TMP-SMX) or atovaquone, none have been found to be superior to pyr-sulf, and no regimen is active against the latent stage of the infection. Furthermore, the efficacy of these regimens against ocular disease remains uncertain. In multiple studies, systematic screening for infection during gestation, followed by treatment with spiramycin for acute maternal infections and with pyr-sulf for those with established fetal infection, has been shown to be effective at preventing vertical transmission and minimizing the severity of congenital toxoplasmosis (CT). Despite significant progress in treating human disease, there is a strong impetus to develop novel therapeutics for both the acute and latent forms of the infection. Here we present an overview of toxoplasmosis treatment in humans and in animal models. Additional research is needed to identify novel drugs by use of innovative high-throughput screening technologies and to improve experimental models to reflect human disease. Such advances will pave the way for lead candidates to be tested in thoroughly designed clinical trials in defined patient populations.

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Section: Introductionmentioning

confidence: 99%

Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice

et al. 2018

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“…Because of this, there is an imperative need for new therapeutics to be developed to combat acute infection. No FDA approved treatment has yet to be established for congenital toxoplasmosis, but it has been treated with clindamycin with varying degrees of success ( McFarland et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii

Sanford

Schulze

Potluri

et al. 2018

International Journal for Parasitology: Drugs and Drug Resistan

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Toxoplasma gondii is an obligate intracellular parasite with global incidence. The acute infection, toxoplasmosis, is treatable but current regimens have poor host tolerance and no cure has been found for latent infections. This work builds upon a previous high throughput screen which identified benzoquinone acyl hydrazone (KG8) as the most promising compound; KG8 displayed potent in vitro activity against T. gondii but only marginal in vivo efficacy in a T. gondii animal model. To define the potential of this new lead compound, we now describe a baseline structure-activity relationship for this chemotype. Several derivatives displayed IC50's comparable to that of the control treatment pyrimethamine with little to no cytotoxicity. The best of these, KGW44 and KGW59, had higher metabolic stability than KG8. In an in vivo T. gondii murine model, KGW59 significantly increased survivorship. This work provides new insights for optimization of this novel chemotype.

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“…Moreover, histone deacetylase is potentially a very important drug target in T. gondii , since scriptaid and trichostatin A had the highest effect against T. gondii tachyzoite proliferation with the IC 50 of 0.039 and 0.041 μM, respectively (Strobl et al, 2007). For promising anti- T. gondii drugs/compounds, assessment of their ability to control parasite growth is a key step in drug development (McFarland et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

et al. 2017

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The currently available anti-Toxoplasma agents have serious limitations. This systematic review was performed to evaluate drugs and new compounds used for the treatment of toxoplasmosis. Data was systematically collected from published papers on the efficacy of drugs/compounds used against Toxoplasma gondii (T. gondii) globally during 2006–2016. The searched databases were PubMed, Google Scholar, Science Direct, ISI Web of Science, EBSCO, and Scopus. One hundred and eighteen papers were eligible for inclusion in this systematic review, which were both in vitro and in vivo studies. Within this review, 80 clinically available drugs and a large number of new compounds with more than 39 mechanisms of action were evaluated. Interestingly, many of the drugs/compounds evaluated against T. gondii act on the apicoplast. Therefore, the apicoplast represents as a potential drug target for new chemotherapy. Based on the current findings, 49 drugs/compounds demonstrated in vitro half-maximal inhibitory concentration (IC50) values of below 1 μM, but most of them were not evaluated further for in vivo effectiveness. However, the derivatives of the ciprofloxacin, endochin-like quinolones and 1-[4-(4-nitrophenoxy) phenyl] propane-1-one (NPPP) were significantly active against T. gondii tachyzoites both in vitro and in vivo. Thus, these compounds are promising candidates for future studies. Also, compound 32 (T. gondii calcium-dependent protein kinase 1 inhibitor), endochin-like quinolones, miltefosine, rolipram abolish, and guanabenz can be repurposed into an effective anti-parasitic with a unique ability to reduce brain tissue cysts (88.7, 88, 78, 74, and 69%, respectively). Additionally, no promising drugs are available for congenital toxoplasmosis. In conclusion, as current chemotherapy against toxoplasmosis is still not satisfactory, development of well-tolerated and safe specific immunoprophylaxis in relaxing the need of dependence on chemotherapeutics is a highly valuable goal for global disease control. However, with the increasing number of high-risk individuals, and absence of a proper vaccine, continued efforts are necessary for the development of novel treatment options against T. gondii. Some of the novel compounds reviewed here may represent good starting points for the discovery of effective new drugs. In further, bioinformatic and in silico studies are needed in order to identify new potential toxoplasmicidal drugs.

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Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

Cited by 37 publications

References 199 publications

Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice

Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice

Derivatives of a benzoquinone acyl hydrazone with activity against Toxoplasma gondii

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

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