Antikinetoplastid Antimitotic Activity and Metabolic Stability of Dinitroaniline Sulfonamides and Benzamides

Bioorg Med Chem. 2006 Aug 15;14(16):5699-710. doi: 10.1016/j.bmc.2006.04.017. Epub 2006 May 3.

Abstract

N(1)-Phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide (1) and N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (2) show potent in vitro antimitotic activity against kinetoplastid parasites but display poor in vivo activity. Seventeen new dinitroaniline sulfonamide and eleven new benzamide analogs of these leads are reported here. Nine of the sulfonamides display in vitro IC(50) values under 500 nM against African trypanosomes, and the most active antikinetoplastid compounds also inhibit the in vitro assembly of purified leishmanial tubulin with potencies similar to that of 2. While several of the potent compounds are rapidly degraded by rat liver S9 fractions in vitro, N(1)-(3-hydroxy)phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (21) displays an IC(50) value of 260 nM against African trypanosomes in vitro and is more stable than 2 in the in vitro metabolism assay.

Publication types

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

MeSH terms

  • Animals
  • Antimitotic Agents / chemical synthesis
  • Antimitotic Agents / pharmacology*
  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / pharmacology*
  • Inhibitory Concentration 50
  • Kinetoplastida / drug effects*
  • Leishmania donovani / drug effects*
  • Liver / metabolism
  • Rats
  • Structure-Activity Relationship
  • Sulfanilamides / chemical synthesis
  • Sulfanilamides / pharmacology*
  • Trypanosoma / drug effects*
  • Tubulin / metabolism

Substances

  • Antimitotic Agents
  • Antiprotozoal Agents
  • Benzamides
  • Sulfanilamides
  • Tubulin