Antimalarial Drugs – What is in Use and What is in the Pipeline

Schlitzer, Martin

doi:10.1002/ardp.200700184

Cited by 131 publications

(92 citation statements)

References 186 publications

(121 reference statements)

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“…Although our understanding of the parasite's biology has increased now that the sequence of the Plasmodium genome is available (43), few new drug targets or classes of drugs have been validated (44,45), and current therapies seem to be insufficient for malaria elimination (45)(46)(47). Major antimalarial efforts during the last few years include strategies as diverse as the use of combination therapy; the development of analogs of existing agents; the discovery of natural products inhibitors; compound reprofiling; the evaluation of drug resistance reversers; and the consideration of new chemotherapeutic agents (30,31,44,48,49).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…These compounds belong to four categories, including the 4-or 8-aminoquinoline group, the antifolate group, the artemisinin group and the hydroxynapthoquinone/atovaquone group (Croft et al 2002;Popov et al 2003;Schlitzer 2008). …”

Section: General Introduction Of Malaria and Current Malaria Control mentioning

confidence: 99%

Evaluation of novel carbamate insecticides for neurotoxicity to non-target species

Jiang

Swale

Carlier

et al. 2013

Pesticide Biochemistry and Physiology

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Malaria (vector: Anopheles gambiae) is a major infectious disease that kills about 1 million people each year. For the improvement of its treatment and vector control during the past decades, several issues such as high medicine cost, insecticide resistance, and lack of an effective vaccine have prevented adequate control of malaria. Additionally, the low selectivity of malaria vector insecticides also presents a public health problem. The purpose of developing novel carbamate insecticides in our laboratory is to offer effective and selective insecticide options to achieve the ultimate goal of malaria control.First, 50% inhibition concentration (IC 50 ) data was collected from three mammalian AChEs with eight commercial carbamate insecticides by using the Ellman assay. The IC 50 values varied from 57 nM to 7358 nM. The AChE sensitivity pattern and level were shown to be similar between the recombinant mouse and ICR male mouse brain cortex homogenate (slope = 0.99, R 2 = 0.96).Then eight novel carbamate insecticides that are possible malaria vector control agents were selected for further neurotoxicity testing in non-target organisms. Neurotoxic esterase (NTE) assay showed that the novel carbamates did not significantly inhibit NTE, inhibition of which underlies a significant hazard for anticholinesterases, especially organophosphates, in several nontarget vertebrate organisms. The NTE activity in the presence of novel carbamate insecticides ranged from 93% to 116% of the control, while in the commercial group, bendiocarb significantly inhibited NTE, leaving only 76.5% of the initial reactivity at 1 mM inhibitor concentration.Further in vivo bioassay using Daphnia magna was conducted to compare the aquatic toxicity of commercial and novel carbamates. The data showed that except for PRC331 (3-tertbutylphenylmethylcarbamate), all novel carbamates were of similar potency as bendiocarb (LC 50 = 611 nM) for aquatic toxicity, and their LC 50 values ranged from 172 nM (PRC331) to 1109 nM.In conclusion, the novel carbamate insecticides would appear to be an improvement over commercial carbamate insecticides because of greater selectivity, negligible NTE inhibition capacity, but in some cases with potent in vivo toxicity to Daphnia magna. However, since the envisioned usage of these compounds is in bednets or as indoor residual sprays (IRS), any environmental exposures to nontarget aquatic organisms are expected to be minimal.iv ACKNOWLEDGEMENTS

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“…The global antimalarial drug discovery portfolio has significantly improved over the last 15 years. [6][7][8][9] In part this is attributable to the coordinative work of the Medicines for Malaria Venture (MMV) and the Drugs for Neglected Diseases initiative (DNDi) which were both established in 1999. Amongst others, the Bill and Melinda Gates foundation has made significant financial contribution to aid this work.…”

Section: Introductionmentioning

confidence: 99%

Continuous flow synthesis of antimalarials: opportunities for distributed autonomous chemical manufacturing

2017

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The concept of distributed manufacturing of chemicals is presented and discussed, with specific focus on the context of preparing molecules that can combat the development of geographically-localised resistant strains of infectious pathogens. Specifically we present the case of antimalarial compounds and demonstrate that the flow chemistry community have already designed both a machine capable of distrubuted chemical manufacturing and a module that would be capable of producing artemisin derivatives at the point of use.

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Antimalarial Drugs – What is in Use and What is in the Pipeline

Cited by 131 publications

References 186 publications

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

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

Evaluation of novel carbamate insecticides for neurotoxicity to non-target species

Continuous flow synthesis of antimalarials: opportunities for distributed autonomous chemical manufacturing

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