Synthesis, DNA affinity, and antiprotozoal activity of linear dications: Terphenyl diamidines and analogues

J Med Chem. 2006 Aug 24;49(17):5324-32. doi: 10.1021/jm060470p.

Abstract

Diamidines 10a-g and 18a,b were obtained from dinitriles 9a-g and 15a,b by treatment with lithium trimethylsilylamide or upon hydrogenation of bis-O-acetoxyamidoximes. Dinitriles 9a-g were prepared via Suzuki reactions between arylboronic acids and arylnitriles. Potential prodrugs 12a-f and 17 were prepared via methylation of the diamidoximes 11a-f and 16a. Significant DNA affinities for rigid-rod molecules were observed. Compounds 10a, 10b, 10d, 18a, and 18b show IC50 values of 5 nM or less against Trypanosoma brucei rhodesiense (T. b. r.) and 10a, 10b, 10e, 18a, and 18b gave similar ones against Plasmodium falciparum (P.f.). The dications, 10a, 10d, 10f, and 10g are more active than furamidine in vivo. The prodrugs are only moderately effective on oral administration. Mouse liver microsome bioconversion of the methamidoxime prodrugs is significantly reduced from that of pafuramidine and suggests that the in vivo efficacy of these prodrugs is, in part, due to poor bioconversion.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Antiprotozoal Agents* / administration & dosage
  • Antiprotozoal Agents* / chemical synthesis
  • Antiprotozoal Agents* / pharmacology
  • Biotransformation
  • Cations / chemistry
  • DNA / drug effects*
  • Drug Stability
  • In Vitro Techniques
  • Liver / drug effects
  • Mice
  • Microsomes / drug effects
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Pentamidine* / administration & dosage
  • Pentamidine* / chemical synthesis
  • Pentamidine* / pharmacology
  • Plasmodium falciparum / drug effects
  • Prodrugs* / administration & dosage
  • Prodrugs* / chemical synthesis
  • Prodrugs* / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Terphenyl Compounds* / administration & dosage
  • Terphenyl Compounds* / chemical synthesis
  • Terphenyl Compounds* / pharmacology
  • Trypanosoma brucei rhodesiense / drug effects

Substances

  • Antiprotozoal Agents
  • Cations
  • Prodrugs
  • Terphenyl Compounds
  • Pentamidine
  • DNA