Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and Study of the Antimalarial Cardamom Peroxide.

ABSTRACT: A full account of our previously disclosed synthesis of the monoterpene dimer cardamom peroxide is reported. Inspired by hypotheses regarding the potential biosynthetic origins of this natural product, several unproductive routes are also reported. The chemical reactivity of this structurally unique metabolite in the presence of iron(II) sources is also reported as is its antimalarial activity against Plasmodium falciparum clinical isolates from several Cambodian provinces.

SUBMITTER: Hu X

PROVIDER: S-EPMC6181145 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis and Study of the Antimalarial Cardamom Peroxide.

Hu Xirui X Lim Pharath P Fairhurst Rick M RM Maimone Thomas J TJ

Tetrahedron 20180326 26

A full account of our previously disclosed synthesis of the monoterpene dimer cardamom peroxide is reported. Inspired by hypotheses regarding the potential biosynthetic origins of this natural product, several unproductive routes are also reported. The chemical reactivity of this structurally unique metabolite in the presence of iron(II) sources is also reported as is its antimalarial activity against <i>Plasmodium falciparum</i> clinical isolates from several Cambodian provinces. ...[more]

PMID: 30319159

Similar Datasets

Four-step synthesis of the antimalarial cardamom peroxide via an oxygen stitching strategy.

Project description:A four-step synthesis of the antimalarial terpene cardamom peroxide, a 1,2-dioxepane-containing natural product, is reported from (-)-myrtenal and molecular oxygen. This highly concise route was guided by biosynthetic logic and enabled by an unusual manganese-catalyzed, tandem hydroperoxidation reaction. The absolute configuration of the cardamom peroxide is reported, and its mode of fragmentation following Fe(II)-mediated endoperoxide reduction is established. These studies reveal the generation of reactive intermediates distinct from previously studied endoperoxide natural products.

| S-EPMC4353017 | biostudies-literature

Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439.

Project description:OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine N-oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug-drug interactions and support physiologically based pharmacokinetic (PBPK) modeling.

| S-EPMC8802618 | biostudies-literature

Novel interactions of cardamom mosaic virus VPg with cardamom histones H3 and H4.

Project description:The host genome targeting potyviral proteins is sparsely reported. Viral genome-linked protein (VPg) is a multifaceted protein known for its interactions with a suite of host proteins, guides essential viral life cycle processes such as genome replication, translation, genome packing, and antiviral defence. Besides, VPg also plays a crucial role in assisting the transport of nuclear inclusion a protease (NIa protease) into the host nucleus. Apart from that, the role of VPg in the nucleus of the cognate host is not clear. Although NIa protease has been reported for DNase activity, the molecular mechanisms underlying host genome accessibility are not yet understood completely. Here, we employed yeast two hybrid assays to test the cardamom histones H3 and H4 interaction with the VPg and NIa protease of macluravirus cardamom mosaic virus (CdMV). Although CdMV NIa protease has the putative histone-binding ER motif of MYST histone acetyltransferase, it did not interact with host histones H3 and H4. Surprisingly, CdMV VPg displayed strong interaction with histone proteins H3 and H4. Leucine prototrophy and β-galactosidase assays were performed which validated VPg interaction with histones. To the best of our knowledge, this study is the first report for the multipartnered potyvirid protein VPg interaction with host histones H3 and H4.

| S-EPMC7501347 | biostudies-literature

Synthesis of New Triazolopyrazine Antimalarial Compounds.

Project description:A radical approach to late-stage functionalization using photoredox and Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC50 values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM.

| S-EPMC8122397 | biostudies-literature

Peroxide Antimalarial Drugs Target Redox Homeostasis in <i>Plasmodium falciparum</i> Infected Red Blood Cells.

Project description:Plasmodium falciparum causes the most lethal form of malaria. Peroxide antimalarials based on artemisinin underpin the frontline treatments for malaria, but artemisinin resistance is rapidly spreading. Synthetic peroxide antimalarials, known as ozonides, are in clinical development and offer a potential alternative. Here, we used chemoproteomics to investigate the protein alkylation targets of artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, artefenomel. We greatly expanded the list of proteins alkylated by peroxide antimalarials and identified significant enrichment of redox-related proteins for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed by dynamic live imaging of the glutathione redox potential using a genetically encoded redox-sensitive fluorescence-based biosensor. Targeted liquid chromatography-mass spectrometry (LC-MS)-based thiol metabolomics also confirmed changes in cellular thiol levels. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.

| S-EPMC8762662 | biostudies-literature

Synthesis, antileishmanial, antimalarial evaluation and molecular docking study of some hydrazine-coupled pyrazole derivatives.

Project description:Pyrazole-bearing compounds are known for their diverse pharmacological effects including potent antileishmanial and antimalarial activities. Herein, some hydrazine-coupled pyrazoles were successfully synthesized and their structures were verified by employing elemental microanalysis, FTIR, and 1H NMR techniques. The in vitro antileishmanial and in vivo antimalarial activities of the synthesized pyrazole derivatives (9-15) were evaluated against Leishmania aethiopica clinical isolate and Plasmodium berghei infected mice, respectively. The result revealed that compound 13 displayed superior antipromastigote activity (IC50 = 0.018) that was 174- and 2.6-fold more active than the standard drugs miltefosine (IC50 = 3.130) and amphotericin B deoxycholate (IC50 = 0.047). The molecular docking study conducted on Lm-PTR1, complexed with Trimethoprim was acquired from the Protein Data Bank (PDB ID:2bfm), justified the better antileishmanial activity of compound 13. Furthermore, the target compounds 14 and 15 elicited better inhibition effects against Plasmodium berghei with 70.2% and 90.4% suppression, respectively. In conclusion, the hydrazine-coupled pyrazole derivatives may be considered potential pharmacophores for the preparation of safe and effective antileishmanial and antimalarial agents.

| S-EPMC10775556 | biostudies-literature

Peroxide antimalarial drugs impact redox homeostasis in Plasmodium falciparum infected red blood cells

Project description:Plasmodium falciparum causes the most lethal form of malaria. The frontline treatments for this severe disease are combination therapies based on semisynthetic peroxide antimalarials, known as artemisinins. There is growing resistance to artemisinins and new drugs with novel mechanisms of action are urgently required. Synthetic peroxide antimalarials, known as ozonides, exhibit potent antimalarial activity both in vitro and in vivo. Here, we used chemical proteomics to investigate the protein alkylation targets of clickable artemisinin and ozonide probes, including an analogue of the ozonide clinical candidate, OZ439. We greatly expanded the list of protein targets for peroxide antimalarials and identified redox processes as being significantly enriched from the list of protein targets for both artemisinins and ozonides. Disrupted redox homeostasis was confirmed with the use of a genetically encoded fluorescence-based biosensor comprising a redox-sensitive GFP (roGFP) fused to human glutaredoxin 1. This facilitated specific and dynamic live imaging of the glutathione redox potential in the cytosol of peroxide-treated infected red blood cells with high sensitivity and temporal resolution. We also used a targeted LC-MS based thiol metabolomics assay to accurately measure relative changes in cellular thiol levels (including thiol metabolites, glutathione precursors and oxidised and reduced glutathione) within peroxide-treated P. falciparum-infected red blood cells. This work shows that peroxide antimalarials disproportionately alkylate proteins involved in redox homeostasis and that disrupted redox processes are involved in the mechanism of action of these important antimalarials.

2022-02-17 | PXD027334 | Pride

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Project description:Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

| S-EPMC5515376 | biostudies-literature

Synthesis and potent antimalarial activity of kalihinol B.

Project description:Of the 50+ kalihinane diterpenoids reported to date, only five had been tested for antimalarial activity, in spite of the fact that kalihinol A is the most potent among the members of the larger family of antimalarial isocyanoterpenes. We have validated a strategy designed to access many of the kalihinanes with a 12-step enantioselective synthesis of kalihinol B, the tetrahydrofuran isomer of kalihinol A (a tetrahydropyran). Kalihinol B shows similarly high potency against chloroquine-resistant Plasmodium falciparum.

| S-EPMC4415034 | biostudies-literature

High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine.

Project description:Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API's) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria.

| S-EPMC5852550 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data