Synthesis and monoamine oxidase inhibitory activity of new pyridazine-, pyrimidine- and 1,2,4-triazine-containing tricyclic derivatives

J Med Chem. 2007 Nov 1;50(22):5364-71. doi: 10.1021/jm070728r. Epub 2007 Oct 2.

Abstract

A number of condensed azines, mostly belonging to the families of indeno-fused pyridazines (1), pyrimidines (2, 3), and 1,2,4-triazines (4, 5), were synthesized and evaluated in vitro as monoamine oxidase (MAO) A and B inhibitors. Most of them showed higher inhibition potency toward MAO-B, the most effective one being 3-(3-nitrophenyl)-9H-indeno[1,2-e] [1,2,4]triazin-9-one (4c), which displayed an IC50 value of 80 nM and proved to be 10-fold more potent than its [2,1-e] fusion isomer 5. Replacing the 3-phenyl group of the known indeno[1,2-c]pyridazin-5-one MAO-B inhibitors with a flexible phenoxymethyl group enhanced the inhibitory potency. The inhibition data highlighted the importance of the aza-heterocyclic scaffold in affecting the MAO isoform selectivity. The 3-phenyl derivatives with type 1, 4, and 5 scaffolds were inhibitors of MAO-B with little or no MAO-A effect, whereas 2- or 3-phenyl derivatives of type 2 and 3 pyrimidine-containing fusion isomers inhibited both isoenzymes with a structure-dependent preference toward MAO-A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Brain / enzymology
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Models, Molecular
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology
  • Pyridazines / chemical synthesis*
  • Pyridazines / chemistry
  • Pyridazines / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Quantitative Structure-Activity Relationship
  • Rats
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology

Substances

  • 3-(3-nitrophenyl)-9H-indeno(1,2-e)(1,2,4)triazin-9-one
  • Heterocyclic Compounds, 3-Ring
  • Isoenzymes
  • Monoamine Oxidase Inhibitors
  • Pyridazines
  • Pyrimidines
  • Triazines