A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

Bajsa, Joanna; Singh, Kshipra; Nanayakkara, Dhammika; Duke, Stephen O.; Rimando, Agnes M.; Evidente, Antonio; Tekwani, Babu L.

doi:10.1248/bpb.30.1740

Cited by 35 publications

(35 citation statements)

References 46 publications

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“…Another interesting feature of commercial agrochemicals is the very low production cost of only a few cent/g, as the compounds are produced in highly optimized processes on the multi-ton scale. Surprisingly, these aspects have not led to a systematic evaluation of agrochemicals for pharmacological use so far [26].…”

Section: Introductionmentioning

confidence: 99%

Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease

Witschel¹,

Rottmann

Kaiser

et al. 2012

PLoS Negl Trop Dis

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In tropical regions, protozoan parasites can cause severe diseases with malaria, leishmaniasis, sleeping sickness, and Chagas disease standing in the forefront. Many of the drugs currently being used to treat these diseases have been developed more than 50 years ago and can cause severe adverse effects. Above all, resistance to existing drugs is widespread and has become a serious problem threatening the success of control measures. In order to identify new antiprotozoal agents, more than 600 commercial agrochemicals have been tested on the pathogens causing the above mentioned diseases. For all of the pathogens, compounds were identified with similar or even higher activities than the currently used drugs in applied in vitro assays. Furthermore, in vivo activity was observed for the fungicide/oomyceticide azoxystrobin, and the insecticide hydramethylnon in the Plasmodium berghei mouse model, and for the oomyceticide zoxamide in the Trypanosoma brucei rhodesiense STIB900 mouse model, respectively.

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Section: Introductionmentioning

confidence: 99%

Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease

Witschel¹,

Rottmann

Kaiser

et al. 2012

PLoS Negl Trop Dis

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“…A number of herbicides and phytotoxins with known molecular targets in the plastid have been evaluated for antimalarial activity 2–4. Various phytotoxins released by plant pathogenic fungi are known 5–7 to inhibit metabolic pathways in the apicoplast 8.…”

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confidence: 99%

Bioactive 1,4-Dihydroxy-5-phenyl-2-pyridinone Alkaloids from Septoria pistaciarum

et al. 2010

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Four new 1,4-dihydroxy-5-phenyl-2-pyridinone alkaloids (1-4) were isolated from an EtOAc extract of a culture medium of Septoria pistaciarum. The structures of these compounds were determined by spectroscopic methods, and the absolute configuration of the major compound (1) by X-ray crystallographic analysis. Compound 1 exhibited moderate in vitro antiplasmodial (antimalarial) activity against chloroquine-sensitive (D6) and -resistant (W2) strains of Plasmodium falciparum and cytotoxic activity to Vero cells. Compound 2 was moderately active against both methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus.Plant-like metabolic pathways found in the apicoplast,1 a chloroplast-like organelle of Plasmodium species, have been identified as suitable targets in malaria drug discovery. A number of herbicides and phytotoxins with known molecular targets in the plastid have been evaluated for antimalarial activity.2 -4 Various phytotoxins released by plant pathogenic fungi are known 5 -7 to inhibit metabolic pathways in the apicoplast.8 As part of our ongoing search for potential sources of new antimalarial compounds, we have screened a number of plant pathogenic fungi for antiplasmodial activity.Septoria pistaciarum (Ascomycetes) is the causative agent of Septoria leaf and fruit spot disease in pistachio (Pistachia vera) in the US9 and Mediterranean countries.10 An EtOAc extract of this fungus showed potent herbicidal activity and moderate antiplasmodial activity against Plasmodium falciparum albeit with low selectivity index. No previous chemical work has been reported for this species. Bioassay-guided fractionation of the EtOAc extract led to the isolation of a new 1,4-dihydroxy-5-phenyl-2-pyridinone analogue as the active compound. Three additional new but inactive analogues of the same class were also isolated and identified. Several compounds of this class have previously been isolated from a number of fungal species and have shown antibacterial,11 , 12 antitumor,12 antifungal,11 , 13 and neurotrophic14 activities.* To whom correspondence should be addressed. Supporting Information available: NMR spectra of compounds 1-4, single-crystal X-ray structure of compound, and cif files of the X-ray data for compound 1. NIH Public Access Results and DiscussionCompound 1 was isolated as the major active constituent of the EtOAc extract of S. pistaciarum. The molecular formula of 1 was determined as C 22 H 29 NO 4 by HRESIMS. The 13 C NMR spectra confirmed the presence of 22 carbon atoms, which comprised five quaternary, 11 methine, two methylene, and four methyl carbons. The 1 H NMR and COSY spectra displayed six hydrogens in the aromatic region consisting of a one-proton singlet and an A 2 B 2 C system due to a monosubstituted phenyl group. NMR signals in the aromatic region showed close resemblance to those of the 1,4-dihydroxy-5-phenyl-2-pyridinone moiety of the antitumor agent, TMC-69-6H, and its analogues.12 IR absorptions (3109, 1642, and 1556 cm −1 ) and UV maxima (207.1, 241.0, a...

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“…Compounds 5 , 65 6 , 65 7 , 66 9 , 67 27 , 68 85 69 have previously been reported to have anti-Plasmodial activity. Compound 9 had weak activity against P. falciparum 3D7 (61% inhibition at 100 μM) but had a previously reported IC 50 of 9 μM against chloroquine-sensitive (D6, Sierra Leone) and chloroquine-resistant (W2) lines of P. falciparum.…”

Section: Resultsmentioning

confidence: 99%

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

Pedro

Mak

et al. 2018

ACS Infect. Dis.

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Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.

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A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

Cited by 35 publications

References 46 publications

Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease

Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease

Bioactive 1,4-Dihydroxy-5-phenyl-2-pyridinone Alkaloids from Septoria pistaciarum

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

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