Antimalarial drug discovery: efficacy models for compound screening

Fidock, David A.; Rosenthal, Philip J.; Croft, Simon L.; Brun, Reto; Nwaka, Solomon

doi:10.1038/nrd1416

Cited by 739 publications

(785 citation statements)

References 102 publications

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“…Hence, absence of mortality up to an oral dose of 6,000 mg/kg could indicate that the test extracts were safe and this could explain the routine use of the plant by the local people for traditional management of malaria. The standard 4-day suppressive test is a test commonly used for in vivo antimalarial phytochemical screening in which >30% suppression following treatment makes a product to be considered active [13,14]. Accordingly, the crude leaf extract of B. strychnifolia which showed 50% suppression at 500 mg/kg and 85% at 1,000 mg/kg can be classified as active.…”

Section: Discussionmentioning

confidence: 99%

Effect of Crude Leaf Extract of Bauhinia strychnifolia in BALB/c Mice Infected with Plasmodium berghei

Chutoam¹,

Klongthalay²,

Somsak³

2015

Malaria Contr Elimination

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Continuous emergence of antimalarial drug resistant malaria parasites and their rapid spread across the globe warrant urgent search for new antimalarials. Traditional medicinal plants have been the main sources for screening active phytochemicals against malaria. Accordingly, this study was aimed at evaluating the antimalarial activity of crude leaf extract of Bauhinia strychnifolia against Plasmodium berghei infected mice. Aqueous crude leaf extract of B. strychnifolia have been prepared and tested for acute toxicity and antimalarial efficacy in P. berghei ANKA infected BALB/c mice. At three oral doses of 100, 500 and 1,000 mg/kg of extract were safe, chemosuppressive and thus prevented body weight loss, packed cell volume reduction and increased mice mean survival time in a dosedependent manner compared to the untreated control group. The maximum efficacious extract was found at the dose of 1,000 mg/kg which prolonged mean mouse survival past day 26 of infection with all the mice in this group having the highest parasitemia suppression rate (85%). This study suggests that the crude leaf extract of this plant have promising antimalarial activity against P. berghei in a dose dependent manner, which supports the folkloric use of the plant for treating malaria.

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Section: Discussionmentioning

confidence: 99%

Effect of Crude Leaf Extract of Bauhinia strychnifolia in BALB/c Mice Infected with Plasmodium berghei

Chutoam¹,

Klongthalay²,

Somsak³

2015

Malaria Contr Elimination

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“…Selectivity indices of extracts were subsequently calculated on the basis of their antiplasmodial activities (IC 50 ) and HFF cell cytotoxicity (CC 50 The fraction PStw(Ace) that showed no signs of acute toxicity in mice was studied against P. berghei strain B (MRA-406, MR4, ATCC W Manassas Virginia) rodent malaria parasite model that was obtained from BEI Resources (www.beiresources.org). The test was carried out based on the four-day suppressive test described by Fidock et al (2004). Swiss albino mice weighing 20-25 g were put randomly into test and control groups, each group containing five mice and were supplied with adequate amount of mouse cubes and clean drinking water.…”

Section: Cytotoxicity Of Pstw(ace) Sub-fractionsmentioning

confidence: 99%

In vitro and in vivo antiplasmodial activity of extracts from Polyalthia suaveolens, Uvaria angolensis and Monodora tenuifolia (Annonaceae)

Mfopa¹,

Mbouna²,

Tchokouaha³

et al. 2017

Int. J. Bio. Chem. Sci

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The present study aimed at investigating the in vitro and in vivo susceptibility of malaria parasites to crude extracts and fractions from Polyalthia suaveolens, Uvaria angolensis, and Monodora tenuifolia. The ethanolic extracts were partitioned using water, dichloromethane, hexane, and methanol. The most promising fraction was subjected to column chromatography. The antiplasmodial effect of extracts, fractions and subfractions against P. falciparum Chloroquine resistant (PfK1) strain was determined using SYBR green florescence assay. The promising fraction was assessed for cytotoxicity against Human Foreskin Fibroblast (HFF) cells and further for safety in Swiss albino mice and suppressive effect against P. berghei. The methanol sub-fraction of P. suaveolens [PStw(Ace)] showed the highest potency with IC 50 of 3.24 µg/mL. Sub-fraction PS8 from PStw(Ace) was the most active with IC 50 of 4.42 µg/mL. Oral administration of PStw(Ace) at 5000 mg/kg b.w in mice showed no signs of toxicity. Also, it exerted the highest suppressive effect against P. berghei at 400 mg/kg b.w throughout the 4 days experiment. Overall, the results achieved supported the use of the three plants in the traditional treatment of malaria in Cameroon. More interestingly, the PStw(Ace) fraction might be of interest in future development of an antimalarial phytodrug.

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“…yoelii 17XL-infected mice were selected at random for treatment with borrelidin (0.25 mg/kg), borrelidin analogs (0.25 or 6 mg/kg) and chloroquine (6 mg/kg). The tested drugs were prepared at appropriate doses in a final volume of 100 mL of aqueous vehicle containing 7% Tween-80 and 3% ethanol as previously described (64). Control animals, also selected at random, received aqueous vehicle (100 mL) by the same route.…”

Section: Methodsmentioning

confidence: 99%

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Novoa

Camacho

Tor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo.aminoacyl-tRNA synthetase | malaria | drug design | borrelidin | plasmodium

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Antimalarial drug discovery: efficacy models for compound screening

Cited by 739 publications

References 102 publications

Effect of Crude Leaf Extract of Bauhinia strychnifolia in BALB/c Mice Infected with Plasmodium berghei

Effect of Crude Leaf Extract of Bauhinia strychnifolia in BALB/c Mice Infected with Plasmodium berghei

<i>In vitro</i> and <i>in vivo</i> antiplasmodial activity of extracts from <i>Polyalthia suaveolens, Uvaria angolensis and Monodora tenuifolia</i> (Annonaceae)

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

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