Nitroindazole compounds inhibit the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to neurotoxic pyridinium cations by human monoamine oxidase (MAO)

Free Radic Res. 2009 Oct;43(10):975-84. doi: 10.1080/10715760903159170. Epub 2009 Aug 7.


Monoamine oxidase (MAO) B is a mitochondrial enzyme selectively involved in the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to toxic pyridinium cations producing Parkinsonism in animal models. Various synthesized 5-nitroindazoles, 6-nitroindazole and the neuroprotectant 7-nitroindazole were examined as inhibitors of MAO and as antioxidants and radical scavengers. The oxidation of MPTP by human MAO-B and mitochondria was assessed by HPLC. Simple nitroindazoles inhibited MPTP oxidation to 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)) in a competitive and reversible manner. 5-Nitroindazole (IC(50)=0.99 microM, K(i)=0.102 microM) and 6-nitroindazole (IC(50)=2.5 microM) were better inhibitors of human MAO-B than 7-nitroindazole (IC(50)=27.8 microM). 6-Nitroindazole also inhibited MAO-A. Nitroindazole isomers were good hydroxyl radical (OH(*)) scavengers, with 5-nitro-, 6-nitro- and 7-nitroindazole showing similar activity (k approximately 10(10) M(-1) s(-1)). Neuroprotective actions of nitroindazoles (7-nitroindazole) could be linked to their MAO-inhibitory and antiradical properties besides inhibition on nitric oxide synthase (NOS). 5-Nitro- and 6-nitroindazole, previously reported as weak NOS inhibitors, were better inhibitors of human MAO-B and more active against MPTP neurotoxin oxidation (lower MPDP(+) and MPP(+) levels) than 7-nitroindazole and acted as good radical scavengers and could be potential neuroprotective agents in addition to MAO-B inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / antagonists & inhibitors*
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / metabolism*
  • Free Radical Scavengers / pharmacology
  • Humans
  • Indazoles / pharmacology*
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Neuroprotective Agents / pharmacology
  • Oxidation-Reduction / drug effects
  • Pyridinium Compounds / metabolism*


  • Free Radical Scavengers
  • Indazoles
  • Monoamine Oxidase Inhibitors
  • Neuroprotective Agents
  • Pyridinium Compounds
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Monoamine Oxidase