Synthesis and SAR of alkanediamide-linked bisbenzamidines with anti-trypanosomal and anti-pneumocystis activity

Bioorg Med Chem Lett. 2009 Oct 15;19(20):5884-6. doi: 10.1016/j.bmcl.2009.08.073. Epub 2009 Aug 23.

Abstract

A series of alkanediamide-linked bisbenzamidines was synthesized and tested in vitro against a drug-sensitive strain of Trypanosoma brucei brucei, a drug-resistant strain of Trypanosoma brucei rhodesiense and Pneumocystiscarinii. Bisbenzamidines linked with longer alkanediamide chains were potent inhibitors of both strains of T. brucei. However, bisbenzamidines linked with shorter alkanediamide chains were the most potent compounds against P. carinii. N,N'-Bis[4-(aminoiminomethyl)phenyl] hexanediamide, 4 displayed potent inhibition (IC50=2-3 nM) against T. brucei and P. carinii, and was non-cytotoxic in the A549 human lung carcinoma cell line. The inhibitory bioactivity was significantly reduced when the amidine groups in 4 were moved from the para to the meta positions or replaced with amides.

Publication types

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

MeSH terms

  • Amidines / chemical synthesis*
  • Amidines / chemistry
  • Amidines / pharmacology
  • Anilides / chemical synthesis*
  • Anilides / chemistry
  • Anilides / pharmacology
  • Animals
  • Antiprotozoal Agents / chemical synthesis*
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / toxicity
  • Benzamidines / chemical synthesis*
  • Benzamidines / chemistry
  • Benzamidines / toxicity
  • Cell Line, Tumor
  • Diamide / chemistry*
  • Humans
  • Pneumocystis / drug effects
  • Structure-Activity Relationship
  • Trypanosoma brucei brucei / drug effects
  • Trypanosoma brucei rhodesiense / drug effects

Substances

  • Amidines
  • Anilides
  • Antiprotozoal Agents
  • Benzamidines
  • N,N'-bis(4-(aminoiminomethyl)phenyl)hexanediamide
  • Diamide