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A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. falciparum Malaria, and the Ebola Filovirus

  1. Author:
    Opsenica, I.
    Burnett, J. C.
    Gussio, R.
    Opsenica, D.
    Todorovic, N.
    Lanteri, C. A.
    Sciotti, R. J.
    Gettayacamin, M.
    Basilico, N.
    Taramelli, D.
    Nuss, J. E.
    Wanner, L.
    Panchal, R. G.
    Solaja, B. A.
    Bavari, S.

  2. Author Address

    [Burnett, James C.] SAIC Frederick Inc, Target Struct Based Drug Discovery Grp, Natl Canc Inst Frederick, Frederick, MD 21702 USA. [Opsenica, Igor; Solaja, Bogdan A.] Univ Belgrade, Fac Chem, Belgrade 11158, Serbia. [Gussio, Rick] Natl Canc Inst Frederick, Dev Therapeut Program, Frederick, MD 21702 USA. [Opsenica, Dejan; Todorovic, Nina] Inst Chem Technol & Met, Belgrade, Serbia. [Lanteri, Charlotte A.; Sciotti, Richard J.] Walter Reed Army Inst Res, Div Expt Therapeut, Silver Spring, MD 20910 USA. [Gettayacamin, Montip] Armed Forces Res Inst Med Sci, Dept Vet Med, Bangkok 10400, Thailand. [Basilico, Nicoletta; Taramelli, Donatella] Univ Milan, Dipartimento Sanita Pubbl Microbiol Virol, I-20133 Milan, Italy. [Nuss, Jonathan E.; Wanner, Laura; Panchal, Rekha G.; Bavari, Sina] USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA.;Burnett, JC, SAIC Frederick Inc, Target Struct Based Drug Discovery Grp, Natl Canc Inst Frederick, POB B, Frederick, MD 21702 USA.;burnettjames@mail.nih.gov bsolaja@chem.bg.ac.rs sina.bavari@us.army.mil
    1. Year: 2011
    2. Date: Mar
  2. Journal: Journal of Medicinal Chemistry
    1. 54
    2. 5
    3. Pages: 1157-1169
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7-chloroquinolinebased antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum and, in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting beta-hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials and are well tolerated by normal cells. One candidate was also effective when administered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities.

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External Sources

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  2. DOI: 10.1021/jm100938u
  3. View record in Web of Science®
  4. WOS: 000287833300004

Library Notes

  1. Fiscal Year: FY2010-2011
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