Spiroindolones, a Potent Compound Class for the Treatment of Malaria

@article{Rottmann2010SpiroindolonesAP,
  title={Spiroindolones, a Potent Compound Class for the Treatment of Malaria},
  author={Matthias Rottmann and Case W. McNamara and Bryan K. S. Yeung and Marcus C. S. Lee and Bin Zou and Bruce M Russell and Patrick Seitz and David M. Plouffe and Neekesh V. Dharia and Jocelyn Hui Ling Tan and Steven B. Cohen and Kathryn S.R. Spencer and Gonzalo E. Gonz{\'a}lez-P{\'a}ez and Suresh B. Lakshminarayana and Anne En Goh and Rossarin Suwanarusk and Timothy Jegla and Esther K Schmitt and Hans-Peter Beck and Reto Brun and François H. Nosten and Laurent R{\'e}nia and V{\'e}ronique A Dartois and Thomas H. Keller and David A. Fidock and Elizabeth A. Winzeler and Thierry Tidiane Diagana},
  journal={Science},
  year={2010},
  volume={329},
  pages={1175 - 1180}
}
Antimalarial Drug Candidate Spiroindolones were discovered as promising antimalarial drug candidates through a high-throughput screening approach that should be applicable to a range of neglected infectious diseases. Rottmann et al. (p. 1175; see the Perspective by Wells) present the preclinical profile for an optimized spiroindolone drug candidate, NITD609. They obtained evidence for a decrease in drug sensitivity in strains of the malaria parasite Plasmodium falciparum bearing amino acid… 
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References

SHOWING 1-10 OF 43 REFERENCES
Thousands of chemical starting points for antimalarial lead identification
TLDR
Chemical structures and associated data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host–pathogen interaction related targets.
Identification of an antimalarial synthetic trioxolane drug development candidate
TLDR
Here it is described how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.
Chemical genetics of Plasmodium falciparum
TLDR
A phenotypic forward chemical genetic approach to discover new antimalarial chemotypes and structures and biological activity of the entire library are disclosed, many of which showed potent in vitro activity against drug-resistant P. falciparum strains.
In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen
TLDR
An efficient and robust high-throughput cell-based screen based on proliferation of Plasmodium falciparum in erythrocytes, which identified most known antimalarials and many novel chemical scaffolds, which likely act through both known and novel pathways.
Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria
TLDR
The current knowledge about the mode of action of ACTs, their pharmacological properties and the proposed mechanisms of drug resistance are discussed.
Artemisinin resistance in Plasmodium falciparum malaria.
TLDR
P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand, and resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing.
Drug resistance and genetic mapping in Plasmodium falciparum
TLDR
Strategies and issues related to mapping genes contributing to drug resistance in the human malaria parasite Plasmodium falciparum are discussed.
New medicines to improve control and contribute to the eradication of malaria.
TLDR
Recent advances in genome-based technologies and in in vitro screening of whole parasites have broadened the range of therapeutic targets and are accelerating the development of a new generation of treatments for both malaria control and eradication.
Antimalarial drug discovery: efficacy models for compound screening
TLDR
Different in vitro and in vivo screens for antimalarial drug discovery are suggested and a streamlined process for evaluating new compounds on the path from drug discovery to development is recommended.
Variations in frequencies of drug resistance in Plasmodium falciparum.
  • P. Rathod, T. McErlean, P. Lee
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
Continual exposure of malarial parasite populations to different drugs may have selected not only for resistance to individual drugs but also for genetic traits that favor initiation of resistance to
...
...