Synthesis, Biological Evaluation, and Molecular Modeling of 3,5-substituted-N1-phenyl-N4,N4-di-n-butylsulfanilamides as Antikinetoplastid Antimicrotubule Agents

Bioorg Med Chem. 2007 Sep 15;15(18):6071-9. doi: 10.1016/j.bmc.2007.06.042. Epub 2007 Jun 27.

Abstract

Dinitroanilines are of interest as antiprotozoal lead compounds because of their selective activity against the tubulin of these organisms, but concern has been raised due to the potentially mutagenic nitro groups. Analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (GB-II-150, compound 2b), a selective antimitotic agent against African trypanosomes and Leishmania, have been prepared where the nitro groups are replaced with amino, chloro, cyano, carboxylate, methyl ester, amide, and methyl ketone moieties. Dicyano compound 5 displays IC(50) values that are comparable to 2b against purified leishmanial tubulin assembly (6.6 vs 7.4 microM), Trypanosoma brucei brucei growth in vitro (0.26 vs 0.18 microM), Leishmania donovani axenic amastigote growth in vitro (4.4 vs 2.3 microM), and in vitro toxicity against Vero cells (16 vs 9.7 microM). Computational studies provide a rationale for the antiparasitic order of activity of these analogues and further insight into the role of the substituents at the 3 and 5 positions of the sulfanilamide ring.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Kinetoplastida / drug effects*
  • Kinetoplastida / metabolism
  • Kinetoplastida / parasitology
  • Leishmania donovani / drug effects*
  • Leishmania donovani / metabolism
  • Leishmania donovani / parasitology
  • Microtubules / drug effects*
  • Microtubules / metabolism
  • Microtubules / parasitology
  • Models, Chemical
  • Models, Molecular
  • Structure-Activity Relationship
  • Sulfanilamides / chemical synthesis*
  • Sulfanilamides / chemistry
  • Sulfanilamides / pharmacology
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosomiasis, African / drug therapy
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology

Substances

  • Sulfanilamides
  • Trypanocidal Agents
  • Tubulin Modulators