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Author Notes:

Tel: 404-727-9157. E-mail: mnatchu@emory.edu.

Author Contributions: The manuscript was written through contributions of E.M., J.J.H., D.S.M., R.B.H., M.R.G., and M.G.N. All authors have given approval to the final version of the manuscript.

The consulting input and assistance of John W. Barnwell, Ketan Desai, and James Sikorski are gratefully acknowledged.

We are also grateful to Suzanne Mays for input on the design of the biological testing protocols.

The authors declare no competing financial interest.

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Research Funding:

We gratefully acknowledge financial support from The Emory Institute for Drug Discovery, Emory University.

Keywords:

  • Enigmols
  • sphingolipids
  • malaria
  • drugs
  • antimalarials
  • Plasmodium

Sphingolipid AnaloguesInhibit Development of MalariaParasites

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Journal Title:

ACS Medicinal Chemistry Letters

Volume:

Volume 3, Number 1

Publisher:

, Pages 43-47

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Plasmodium-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species Plasmodium falciparum and Plasmodium knowlesi, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo.

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© 2011 American ChemicalSociety

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