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

Stec, Jozef; Fomovska, Alina; Afanador, Gustavo A.; Muench, Stephen P.; Zhou, Ying; Lai, Bo Shiun; Bissati, Kamal El; Hickman, Mark; Lee, Patricia; Leed, Susan E.; Auschwitz, Jennifer M.; Sommervile, Caroline; Woods, Stuart; Roberts, Craig W.; Rice, David W.; Prigge, Sean T.; McLeod, Rima; Kozikowski, Alan P.

doi:10.1002/cmdc.201300050

Cited by 20 publications

(24 citation statements)

References 74 publications

(91 reference statements)

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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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“… 96 , 97 Triclosan has a very low solubility in water and poor oral bioavailability and a number of triclosan derivatives have been synthesized to increase potency and solubility. 98 – 100 The most promising triclosan derivatives are described by Stec et al; 98 compound 16c of this series had an in vitro IC 50 of 250 nM compared to 3 µM for triclosan. Compound 16c also demonstrated improved solubility over triclosan, with a computational log P of 3.9 versus 5.5 for triclosan.…”

Section: Fatty Acid Synthesis Inhibitorsmentioning

confidence: 99%

Drugs in development for toxoplasmosis: advances, challenges, and current status

Alday

Doggett

2017

DDDT

254

243

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Toxoplasma gondii causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against T. gondii tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.

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“…These analogs were previously evaluated for biological activity against Bacillus anthracis [39] and Toxoplasma gondii . [40, 41] …”

Section: Introductionmentioning

confidence: 99%

Biological Evaluation of Potent Triclosan‐Derived Inhibitors of the Enoyl–Acyl Carrier Protein Reductase InhA in Drug‐Sensitive and Drug‐Resistant Strains of Mycobacterium tuberculosis

Stec

Vilchèze

Lun³

et al. 2014

ChemMedChem

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New triclosan (TRC) analogs were evaluated for their activity against the enoyl-acyl carrier protein reductase InhA in Mycobacterium tuberculosis (Mtb). TRC is a well-known inhibitor of InhA and specific modifications to its positions 5 and 4′ afforded twenty-seven derivatives; of these compounds seven derivatives showed an improved potency in comparison to TRC. These analogs were active against both drug-susceptible and drug-resistant Mtb strains. The most active compound in this series, 3, had an MIC value of 0.6 μg/mL (1.5 μM) against wild-type Mtb. At a concentration equal to its MIC, this molecule inhibited the purified InhA enzyme to the extent of 98%, and it showed an IC50 value of 90 nM. Compounds 3 and 14 were able to inhibit the biosynthesis of mycolic acids. Furthermore, mc24914, an Mtb strain overexpressing inhA, was resistant to the compounds 3 and 14, supporting the notion that InhA is the likely molecular target of the TRC derivatives presented herein.

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

Cited by 20 publications

References 74 publications

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

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

Drugs in development for toxoplasmosis: advances, challenges, and current status

Biological Evaluation of Potent Triclosan‐Derived Inhibitors of the Enoyl–Acyl Carrier Protein Reductase InhA in Drug‐Sensitive and Drug‐Resistant Strains of Mycobacterium tuberculosis

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