Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase

Cheng, Gang; Muench, Stephen P.; Zhou, Ying; Afanador, Gustavo A.; Mui, Ernest; Fomovska, Alina; Lai, Bo Shiun; Prigge, Sean T.; Woods, Stuart; Roberts, Craig W.; Hickman, Mark; Lee, Patricia; Leed, Susan E.; Auschwitz, Jennifer M.; Rice, David W.; McLeod, Rima

doi:10.1016/j.bmcl.2013.02.019

Cited by 22 publications

(24 citation statements)

References 33 publications

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“…For T. gondii, evidence suggests triclosan may indeed act at least partially through inhibition of FabI, with the compound able to abolish FASII-dependent lipoylation of the PDH complex (see Section 3), and over-expression of the enzyme able to decrease the parasite's susceptibility to the drug [85]. Further efforts have therefore been made to optimize these analogs for use against T. gondii, but few have so far proven sufficiently effective against parasites in vivo [149,[155][156][157].…”

Section: Enoyl-acp Reductase (Fabi)mentioning

confidence: 97%

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Shears

Botté

McFadden

2015

Molecular and Biochemical Parasitology

104

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The malaria parasite Plasmodium possesses a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is essential for parasite survival, and harbors several plant-like metabolic pathways including a type II fatty acid synthesis (FASII) pathway. The FASII pathway was discovered in 1998, and much of the early research in the field pursued it as a therapeutic drug target. These studies identified a range of compounds with activity against bloodstage parasites and led to the localization and characterization of most enzymes in the pathway. However, when genetic studies revealed FASII was dispensable in bloodstage parasites, it effectively discounted the pathway as a therapeutic drug target, and suggested these compounds instead interfered with other processes. Interest in FASII then shifted toward its disruption for malaria prophylaxis and vaccine development, with experiments in rodent malaria models identifying a crucial role for the pathway in the parasite's transition from the liver to the blood. Unexpectedly however, the human malaria parasite P. falciparum was recently found to differ from rodent models and require FASII for mosquito stage development. This requirement blocked the production of the FASII-deficient forms that might be used as a genetically attenuated parasite vaccine, suggesting the pathway was also unsuitable as a vaccine target. This review discusses how perception of FASII has changed over time, and presents key findings about each enzyme in the pathway to identify remaining questions and opportunities for malaria control.

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Section: Enoyl-acp Reductase (Fabi)mentioning

confidence: 97%

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Shears

Botté

McFadden

2015

Molecular and Biochemical Parasitology

104

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“…It has been previously shown that the FASII pathway is non essential for malaria during the erythrocytic stage [75,76] . In fact, these studies showed that Pf ENR enzyme was successfully knocked out and the parasites were viable in in vitro culture, showing that this enzyme is dispensable.…”

Section: Resultsmentioning

confidence: 99%

Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl‐Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii

et al. 2013

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Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was utilized to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well-known ENR inhibitor triclosan afforded a series of 29 new analogs. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16a and 16c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against the recombinant TgENR were 43 and 26 nM, respectively. Additionally, 11 other analogs in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16a and 16c are deemed to be an excellent starting point for the development of new medicines to effectively treat Toxoplasma gondii infections.

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“…The literature search identified six enzymes as reasonable targets for discovering anti-Toxoplasma agents: i.e., 3MB8 (purine nucleoside phosphorylase) (13), 1LII (adenosine kinase (14), DHRF (dihydrofolate reductase) (15), 4M84 (calmodulin-domain protein kinase 1) (16), 3AU9 (1-deoxy-D-xylulose-5-phosphate reductoisomerase) (17), and 2O2S (enoyl-acyl carrier reductase) (18). Based on the structures deposited in the Protein Data Bank, we analyzed the binding affinities of the active compound 1 and inactive compound 2 s-triazoles to the active sites of the aforementioned enzymes.…”

mentioning

confidence: 99%

Triazole-Based Compound as a Candidate To Develop Novel Medicines To Treat Toxoplasmosis

Dzitko

Paneth

Plech

et al. 2014

Antimicrob Agents Chemother

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dThis article reports anti-Toxoplasma gondii activity of 3-(thiophen-2-yl)-1,2,4-triazole-5-thione. The compound displayed significant and reproducible antiparasitic effects at nontoxic concentrations for the host cells, with an experimentally determined 50% inhibitory concentration (IC 50 ) at least 30 times better than that of the known chemotherapeutic agent sulfadiazine. Purine nucleoside phosphorylase was defined as the probable target for anti-Toxoplasma activity of the tested compound. These results provide the foundation for future work to develop a new class of medicines to better treat toxoplasmosis. Standard chemotherapy for the treatment of Toxoplasma infections relies on the inhibition of folate metabolism. The protocol recommends synergistic combination of diaminopyrimidines with sulfonamides, supplemented with folinic acid to mitigate the toxic effects of pyrimethamine on bone marrow. For patients with sensitivity to sulfonamines, macrolides and lincosamides are a second class of medications with anti-Toxoplasma activity. The third class of anti-Toxoplasma drugs, which are only occasionally used as a potential substitute, comprises electron transport inhibitors such as atovaquone (1). In all of these situations, drug resistance, high cost, limited efficacy, and side effects of these drugs often result in discontinuation of therapy (2-5). Therefore, new agents with better activity profiles and that are less expensive are needed. One possible class of drugs are s-triazole derivatives, and in this article, we present a newly found triazole-based candidate to develop novel medicines for more effective treatment of toxoplasmosis.The search for agents that are potent and selective against Toxoplasma continues in several laboratories. Numerous inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells have been identified. Examples are pyrimidines, oryzalines, thiazolidinones, berberines, tryptanthrines, thiocyanates, and bisphosphonates (6, 7). Our attention has been focused on the role of s-triazole series as potential new toxoplasmosis therapeutics. We found that 3-(thiophen-2-yl)-1,2,4-triazole-5-thione (compound 1) showed a potent and reproducible antiparasitic effect with no appreciable toxicity to human cells, while 4-ethyl-3-(4-methyl-1,2,3-thiadiazol-5-yl)-1,2,4-triazole-5-thione (compound 2) was inactive.The procedure for synthesis of 3-(thiophen-2-yl)-1,2,4-triazole-5-thione (compound 1) and 4-ethyl-3-(4-methyl-1,2,3-thiadiazol-5-yl)-1,2,4-triazole-5-thione (compound 2), the effects of tested compounds and sulfadiazine on the viability of L929 (ATCC no. CCL-1) and HeLa (ATCC no. CCL-2) cells, and inhibition of Toxoplasma (RH strain; ATCC no. 50174) growth were described elsewhere (8). The effect of tested compounds on the intensity of Toxoplasma gondii proliferation (%) was measured by 2 methods: incorporation of [ 3 H]uracil (Fig. 1) into the T. gondii DNA (9) and quantitative real-time PCR (qRT-PCR) (Fig. 1) (8). The 50% inhibitory concentration (I...

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Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase

Cited by 22 publications

References 33 publications

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl‐Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii

Triazole-Based Compound as a Candidate To Develop Novel Medicines To Treat Toxoplasmosis

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