: We have already published our discovery that xanthones exhibit potent antimalarial activity, even against multi-drug resistant strains of Plasmodium falciparum. Based on our understanding of xanthone mode of action, we have developed a 2nd generation xanthone, 3,6-bis-omega-diethylaminoamyloxyxanthone (C5). C5 is approximately as potent as chloroquine, yet with equal activity against a panel of drug resistant strains. Herein, we propose to develop the 3 rd generation of xanthone anti-malarials, with a long-term view toward clinical trials. The steps toward this goal are: . Evaluate the in vivo efficacy of existing xanthone analogs. This will be investigated in the P. v. vinckei murine model of malaria. The possibility for acute toxicity of xanthones will be investigated in uninfected mice. . Evaluate the in vitro metabolism of C5 by microsomes. This will be investigated with both human and murine derived microsomes. . Optimize the drug structure beginning with C5 for both safety and antimalarial potency. This will be done in a process iterative between in vitro and in vivo testing, molecular modeling, pharmacokinetics, and spectroscopic evidence. . Synthesis and evaluation of 3rd generation compounds. The hallmark of these 3 rd generation xanthones will be improved safety and antimalarial potency. The 3 rd generation compounds will be inexpensive to produce, chemically and metabolically stable, and orally bioavailable. The mode of action of these xanthone-based antimalarial agents is inhibition of hemozoin formation via complexation of heme. Since heme is an immutable biomolecule, it is difficult to envision any simple mutation that could lead to resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI051509-01A2
Application #
6680499
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Coyne, Philip Edward
Project Start
2003-06-15
Project End
2006-11-30
Budget Start
2003-06-15
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$177,500
Indirect Cost
Name
Portland State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
052226800
City
Portland
State
OR
Country
United States
Zip Code
97207
Winter, Rolf W; Kelly, Jane X; Smilkstein, Martin J et al. (2008) Antimalarial quinolones: synthesis, potency, and mechanistic studies. Exp Parasitol 118:487-97
Kelly, Jane X; Winter, Rolf W; Braun, Theodore P et al. (2007) Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye. Exp Parasitol 116:103-10