Project: Research project

Project Details


This proposed research is directed toward the site-specific
delivery of oxidants to malaria-infected erythrocytes. As malaria
parasites and their host erythrocytes are highly susceptible to
oxidant stress, additional oxidant damage to the parasite/host
erythrocyte system may lead to an interruption of the parasite life
cycle. Since chloroquine and related quinoline are selectively
concentrated in the digestive vacuoles of the erythrocytic form of
the malarial parasite, and since infected erythrocytes possess a
specific uptake mechanism for L-isoleucine, nine peroxide,
oxazirane and "redox" analogy of chloroquine, and six peroxide
derivatives of L-isoleucine are proposed as site-specific oxidant
antimalarial. The proposed syntheses of the target quinoline oxidants rely on
two key transformations. The first is a Mannish type condensation
between secondary amines, formaldehyde, and hydroperoxides; and the
second is the peracid oxidation of imines to oxaranes. The L-
isoleucine peroxides will be synthesized using proxide chemistry
adapted to amino acids. The proposed site-specific oxidants will
be evaluated for antimalarial activity against in vitro P
falciparum, and in vivo P. bergh in collaboration with Dr. John
Eaton at the University of Minnesota and the Walter Reed Army
Institute of Research. If an increase in antimalarial activity or
potency is observed consistent with the hypothesis states above,
then experiments with Dr. Eaton will be conducted to assess their
specificity for the infected erythrocyte/parasite system, and to
determine mechanism (s) of oxidant damage. Finally, incorporation
of oxidant functionality into drugs effective against other oxidant
sensitive protozoa may result in superior agents, and extension of
the concept of site-specific delivery of oxidants.
Effective start/end date5/1/8912/31/92


  • National Institutes of Health


  • Medicine(all)
  • Immunology and Microbiology(all)


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