Synthesis and antiprotozoal activity of dicationic 2,6-diphenylpyrazines and aza-analogues

Bioorg Med Chem. 2013 Nov 1;21(21):6732-41. doi: 10.1016/j.bmc.2013.08.006. Epub 2013 Aug 13.

Abstract

Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2 ΔTm values greater than pentamidine, IC50 values: T. b. r. (4.8-37nM) and P. f. (10-52nM). Most diamidines and prodrugs gave cures for STIB900 model (11, 19a and 24b 4/4 cures); 12 3/4 cures for GVR35 model. Metabolic stability half-life values for O-methylamidoxime prodrugs did not correlate with STIB900 results.

Keywords: 2,6-Diarylpyrazines; Antimalarial agents; Antitrypanosomal agents; Diamidines; Prodrugs.

MeSH terms

  • Animals
  • Antiprotozoal Agents / chemical synthesis*
  • Antiprotozoal Agents / therapeutic use
  • Antiprotozoal Agents / toxicity
  • Aza Compounds / chemistry*
  • Cations / chemistry
  • Cell Line
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Mice
  • Myoblasts / cytology
  • Parasitic Sensitivity Tests
  • Pentamidine / chemistry*
  • Pentamidine / therapeutic use
  • Pentamidine / toxicity
  • Plasmodium falciparum / drug effects
  • Poly dA-dT / chemistry
  • Poly dA-dT / metabolism
  • Prodrugs / chemical synthesis*
  • Prodrugs / therapeutic use
  • Prodrugs / toxicity
  • Pyrazines / chemistry*
  • Rats
  • Structure-Activity Relationship
  • Transition Temperature
  • Trypanosoma brucei rhodesiense / drug effects
  • Trypanosomiasis, African / drug therapy

Substances

  • Antiprotozoal Agents
  • Aza Compounds
  • Cations
  • Prodrugs
  • Pyrazines
  • Poly dA-dT
  • Pentamidine