Synthesis and Comparison of Antimalarial Activity of Febrifugine Derivatives Including Halofuginone

Samant, Bhupesh S.; Sukhthankar, Mugdha

doi:10.2174/157340609788185846

Cited by 24 publications

(13 citation statements)

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“…[12] Unfortunately, the high percentage of genes with unknown function (~50%) makes it difficult to predict which genes are selective drug targets. [13] Halofuginone is one of the most potent known inhibitors of the malaria parasite’s blood stage, [11] however, activity against other Plasmodium life stages has not been investigated. Here, we utilized an in vitro infection system to evaluate if the compound targets a process that is essential for the Plasmodium parasite’s liver stage.…”

Section: Resultsmentioning

confidence: 99%

“…[10] Both compounds have been widely recognized for their exceptional activity against blood stage malaria parasites and their unique mode of action that appears distinct form other antimalarials, however, neither compound has been evaluated for activity against liver stage parasites. [11] In this work we discovered that halofuginone has low nanomolar potency, similar to atovaquone, at reducing P. berghei sporozoite load in HepG2 cells. Halofuginone, like primaquine and atovaquone, does not affect sporozoite traversal.…”

Section: Introductionmentioning

confidence: 97%

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Characterization of Plasmodium Liver Stage Inhibition by Halofuginone

2012

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Malaria is a devastating parasitic disease that afflicts one-third of the world’s population. Commonly used malaria drugs address few targets and their efficacy is being undermined by parasite resistance. Most therapeutics target blood stage malaria, while only few compounds are active against malaria’s liver stage, the first stage of the Plasmodium parasite’s life cycle within the human host. The identification of inhibitors active against liver stage malaria would benefit both the development of chemical probes to elucidate the poorly understood biology of this phase of the parasite’s life cycle and potentially provide agents for preventing and eliminating the disease. Here, we report on the development of a live cell parasite traversal assay in 384-well format amenable to high-throughput screening that exploits the wounding of liver cells by the parasite. This method identifies small molecules that may inhibit the parasites actin-myosin motor system. The traversal assay, in addition to established methods, was used to evaluate the activity of halofuginone, a synthetic halogenated derivative of the natural alkaloid febrifugine, against liver stage Plasmodium berghei parasites. Halofuginone was found to inhibit P. berghei sporozoite load in HepG2 cells with an IC50 of 17 nM. While the compound does not affect parasite traversal through human liver cells, an inhibition time course assay indicates that it affects essential processes in both early and late stage parasite development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Characterization of Plasmodium Liver Stage Inhibition by Halofuginone

2012

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“…Roots of the plant Dichroa febrifuga have been used as traditional anti-malarial therapy in China [19][20][21][22][23][24][25][26]. The active component of this plant is a quinazoline-type alkaloid called febrifugine (FF) that possesses potent in vitro anti-malarial activity [17,[19][20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

“…The active component of this plant is a quinazoline-type alkaloid called febrifugine (FF) that possesses potent in vitro anti-malarial activity [17,[19][20][21][22][23][24][25][26]. Halofuginone (HF), a 7-bromo-6-chloro derivative of FF, shows reduced cellular toxicity compared to FF and is being developed as a medicine for scleroderma, besides being explored for use in cancer and fibrotic disease [27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

Jain

Kikuchi

Oshima

et al. 2014

J Struct Funct Genomics

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Aminoacyl-tRNA synthetases (aaRSs) drive protein translation in cells and hence these are essential enzymes across life. Inhibition of these enzymes can halt growth of an organism by stalling protein translation. Therefore, small molecule targeting of aaRS active sites is an attractive avenue from the perspective of developing anti-infectives. Febrifugine and its derivatives like halofuginone (HF) are known to inhibit prolyl-tRNA synthetase of malaria parasite Plasmodium falciparum. Here, we present functional and crystallographic data on P. falciparum prolyl-tRNA synthetase (PfPRS). Using immunofluorescence data, we show that PfPRS is exclusively resident in the parasite cytoplasm within asexual blood stage parasites. The inhibitor HF interacts strongly with PfPRS in a non-competitive binding mode in presence or absence of ATP analog. Intriguingly, the two monomers that constitute dimeric PfPRS display significantly different conformations in their active site regions. The structural analyses presented here provide a framework for development of febrifugine derivatives that can seed development of new anti-malarials.

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“…It provides a useful reaction site to enhance the conversion and selectivity of various reactions [3]. As part of our ongoing research into selectivity improvement in organic synthesis [4][5][6][7][8][9][10][11][12], we have already described improvement in the regioselectivity of chlorination of phenol and o-chlorophenol in the presence of micelles [4]. We now present a study of selectivity enhancement in aromatic halogenation reactions.…”

Section: Introductionmentioning

confidence: 99%

Selectivity enhancement of aromatic halogenation reactions at the micellar interface: effect of highly ionic media

Samant

Bhagwat

2011

Monatsh Chem

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Halogenation (iodination and bromination) of various aromatic compounds has been studied in micellar media in order to observe the effect on regioselectivity and conversion of the reaction. The addition of surfactant causes a change in the chemical shifts of the aromatic proton resonance of phenol which proves the orientation of the aromatic compound on the micellar surface. However, increase in ionic strength of the reaction media affects the selectivity of reaction by disturbing this spatial orientation of the aromatic compound in the micelle. Selectivity towards particular isomers is dependent on the concentration of the surfactant. In bromination of chlorobenzene (deactivated aromatic compound) enhancement in selectivity and conversion towards the para isomer has been observed.

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Synthesis and Comparison of Antimalarial Activity of Febrifugine Derivatives Including Halofuginone

Cited by 24 publications

References 0 publications

Characterization of Plasmodium Liver Stage Inhibition by Halofuginone

Characterization of Plasmodium Liver Stage Inhibition by Halofuginone

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

Selectivity enhancement of aromatic halogenation reactions at the micellar interface: effect of highly ionic media

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