A chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype A light chain, P. falciparum malaria, and the Ebola filovirus

J Med Chem. 2011 Mar 10;54(5):1157-69. doi: 10.1021/jm100938u. Epub 2011 Jan 25.

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-chloroquinoline-based 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 β-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anopheles / parasitology
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Botulinum Toxins, Type A / antagonists & inhibitors*
  • Cell Line
  • Chlorocebus aethiops
  • Chrysenes / chemical synthesis*
  • Chrysenes / chemistry
  • Chrysenes / pharmacology
  • Ebolavirus / drug effects*
  • Hemeproteins / antagonists & inhibitors
  • Malaria / drug therapy
  • Mice
  • Models, Molecular
  • Plasmodium berghei
  • Plasmodium falciparum / drug effects*
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Antimalarials
  • Antiviral Agents
  • Chrysenes
  • Hemeproteins
  • Quinolines
  • hemozoin
  • Botulinum Toxins, Type A