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Structure Mechanism Insights and the Role of Nitric Oxide Donation Guide the Development of Oxadiazole-2-Oxides as Therapeutic Agents against Schistosomiasis

  1. Author:
    Rai, G.
    Sayed, A. A.
    Lea, W. A.
    Luecke, H. F.
    Chakrapani, H.
    Prast-Nielsen, S.
    Jadhav, A.
    Leister, W.
    Shen, M.
    Inglese, J.
    Austin, C. P.
    Keefer, L.
    Arner, E.
    Simeonov, A.
    Maloney, D. J.
    Williams, D. L.
    Thomas, C. J.

  2. Author Address

    Sayed, Ahmed A.; Williams, David L.] Illinois State Univ, Dept Biol Sci, Normal, IL 61790 USA. [Rai, Ganesha, Lea, Wendy A.; Jadhav, Ajit, Leister, William, Shen, Min, Inglese, James, Austin, Christopher P.; Simeonov, Anton, Maloney, David J.; Thomas, Craig J.] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Sayed, Ahmed A.] Ain Shams Univ, Dept Biochem, Cairo, Egypt. [Luecke, Hans F.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Chakrapani, Harinath, Keefer, Larry] NCI, Comparat Carcinogenesis Lab, NIH, Frederick, MD 21702 USA. [Prast-Nielsen, Stefanie, Arner, Elias S. J.] Karolinska Inst, Dept Med Biochem & Biophys, Div Biochem, SE-17177 Stockholm, Sweden. [Williams, David L.] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA.
    1. Year: 2009
  2. Journal: Journal of Medicinal Chemistry
    1. 52
    2. 20
    3. Pages: 6474-6483
  4. Type of Article: Article
  1. Abstract:

    Schistosomiasis is a chronic parasitic disease affecting hundreds of millions of individuals worldwide. Current treatment depends on a single agent, praziquantel, raising concerns of emergence of resistant parasites. Here, we continue our explorations of an oxadiazole-2-oxide class of compounds we recently identified as inhibitors of thioredoxin glutathione reductase (TGR), a selenocysteine-containing flavoenzyme required by the parasite to maintain proper cellular redox balance. Through systematic evaluation of the core molecular structure of this chemotype, we define the essential pharmacophore, establish a link between the nitric oxide donation and TGR inhibition, determine the selectivity for this chemotype versus related reductase enzymes, and present evidence that these agents can be modified to possess appropriate drug metabolism and pharmacokinetic properties. The mechanistic link between exogenous NO donation and parasite injury is expanded and better defined. The results of these studies verify the utility of oxadiazole-2-oxides as novel inhibitors of TGR and as efficacious antischistosomal agents.

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  2. DOI: 10.1021/jm901021k
  3. PMID: 19761212

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