Antimalarial and antileishmanial activities of histone deacetylase inhibitors with triazole-linked cap group

Bioorg Med Chem. 2010 Jan 1;18(1):415-25. doi: 10.1016/j.bmc.2009.10.042. Epub 2009 Oct 27.

Abstract

Histone deacetylase inhibitors (HDACi) are endowed with plethora of biological functions including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. Parsing the structure-activity relationship (SAR) for each disease condition is vital for long-term therapeutic applications of HDACi. We report in the present study specific cap group substitution patterns and spacer-group chain lengths that enhance the antimalarial and antileishmanial activity of aryltriazolylhydroxamates-based HDACi. We identified many compounds that are several folds selectively cytotoxic to the plasmodium parasites compared to standard HDACi. Also, a few of these compounds have antileishmanial activity that rivals that of miltefosine, the only currently available oral agent against visceral leishmaniasis. The anti-parasite properties of several of these compounds tracked well with their anti-HDAC activities. The results presented here provide further evidence on the suitability of HDAC inhibition as a viable therapeutic option to curb infections caused by apicomplexan protozoans and trypanosomatids.

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

  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Antiprotozoal Agents / chemistry*
  • Antiprotozoal Agents / pharmacology*
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Leishmania donovani / drug effects
  • Leishmaniasis / drug therapy
  • Malaria / drug therapy
  • Plasmodium falciparum / drug effects
  • Structure-Activity Relationship
  • Triazoles / chemistry*
  • Triazoles / pharmacology*

Substances

  • Antimalarials
  • Antiprotozoal Agents
  • Histone Deacetylase Inhibitors
  • Triazoles
  • Histone Deacetylases