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Journal article
Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity
Antimicrobial agents and chemotherapy, v 61(1)
27 Dec 2016
PMID: 27799215
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.
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Details
- Title
- Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity
- Creators
- Hangjun Ke - Drexel UniversityJoanne M Morrisey - Drexel UniversityShiwei Qu - University of California, San DiegoOraphin Chantarasriwong - King Mongkut's University of Technology ThonburiMichael W Mather - Drexel UniversityEmmanuel A Theodorakis - University of California, San DiegoAkhil B Vaidya - Drexel University
- Publication Details
- Antimicrobial agents and chemotherapy, v 61(1)
- Publisher
- American Society for Microbiology
- Number of pages
- 14
- Grant note
- AI028398 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) (https://doi.org/10.13039/100000060) CRC-15-380737 / Cancer Research Coordinating Committee TRG5780085 / Thailand Research Fund (TRF) (https://doi.org/10.13039/501100004396)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000394095800013
- Scopus ID
- 2-s2.0-85009243636
- Other Identifier
- 991019168282504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Pharmacology & Pharmacy