Synthesis and Antitubulin Activity of N1- And N4-substituted 3,5-dinitro Sulfanilamides Against African Trypanosomes and Leishmania

J Med Chem. 2004 Mar 25;47(7):1823-32. doi: 10.1021/jm0304461.

Abstract

Thirty analogues of N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-propylsulfanilamide (GB-II-5, compound 3), a new antikinetoplastid antimitotic agent, have been synthesized and evaluated. The addition of simple functional groups to the N1 aromatic ring generally decreases antiparasitic and antimitotic potency, but placement of a dibutyl substituent at the N4 nitrogen to give N(1)-phenyl-3,5-dinitro-N(4),N(4)-di-n-butylsulfanilamide (compound 35) augments antitrypanosomal and antileishmanial activity. Compound 35 possesses IC(50) values of 0.12 and 2.6 microM against cultured T. brucei and L. donovani amastigote-like forms, surpassing the activity of compound 3 against these parasites by 3.4- and 1.9-fold, respectively. Compound 35 inhibits the assembly of leishmanial tubulin with an IC(50) of 6.9 microM and displays antimitotic effects in cultured T. brucei as assessed by flow cytometry, but shows little effect on purified mammalian tubulin, and displays 100-fold selectivity for trypanosomes over two mammalian cell lines. Although 3 and 35 were not effective in initial in vivo antitrypanosomal assays, the in vitro potency and selectivity of these compounds make N(1)-aryl-3,5-dinitro-N(4),N(4)-dialkylsulfanilamides a promising new class of antikinetoplastid agents that act on parasite tubulin.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Leishmania donovani / drug effects*
  • 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*
  • Tubulin / chemistry
  • Tubulin Modulators*

Substances

  • Sulfanilamides
  • Trypanocidal Agents
  • Tubulin
  • Tubulin Modulators