Indole-Substituted Benzothiazoles and Benzoxazoles as Selective and Reversible MAO-B Inhibitors for Treatment of Parkinson's Disease.

Abstract

To develop novel, selective, and reversible MAO-B inhibitors for safer treatment of Parkinson's disease, benzothiazole and benzoxazole derivatives with indole moiety were designed and synthesized. Most of the synthesized compounds showed inhibitory activities against MAO-B and selectivity over MAO-A. The most active compound was compound 5b, 6-fluoro-2-(1-methyl-1H-indol-5-yl)benzo[d]thiazole with an IC50 value of 28 nM with no apparent effect on MAO-A activity at 10 μM. Based on the reversibility assay, compound 5b turned out to be fully reversible with over 95% of recovery of enzyme activity after washout of the compound. Compound 5b showed a reasonable stability in human liver microsomes and did not affect the activities of CYP isozymes, suggesting an absence of high-risk drug-drug interaction. In an in vivo MPTP-induced animal model of Parkinson's disease, oral administration of compound 5b showed neuroprotection of nigrostriatal dopaminergic neurons as revealed by tyrosine hydroxylase staining and prevention of MPTP-induced parkinsonism as revealed by motor behavioral assay of vertical grid test. In summary, the novel, reversible, and selective MAO-B inhibitor compound 5b was synthesized and characterized. We propose compound 5b as an effective therapeutic compound for relieving parkinsonism.

• Authors: Min-Ho Nam, Moosung Park, Hyeri Park, Youngjae Kim, Seulki Yoon, Vikram Shahaji Sawant, Ji Won Choi, Jong-Hyun Park, Ki Duk Park, Sun-Joon Min, C Justin Lee, Hyunah Choo
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 8 Issue 7 Pg. 1519-1529 (07 19 2017) ISSN: 1948-7193 [Electronic] United States
• PMID: 28332824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Benzothiazoles
• Benzoxazoles
• Monoamine Oxidase Inhibitors
• Neuroprotective Agents
• Tyrosine 3-Monooxygenase
• Monoamine Oxidase

Topics

• Administration, Oral
• Animals
• Antiparkinson Agents (chemical synthesis, chemistry, pharmacology)
• Benzothiazoles (chemical synthesis, chemistry, pharmacology)
• Benzoxazoles (chemical synthesis, chemistry, pharmacology)
• Corpus Striatum (drug effects, enzymology, pathology)
• Dopaminergic Neurons (drug effects, enzymology, pathology)
• Humans
• Male
• Mice, Inbred C57BL
• Microsomes, Liver (drug effects, enzymology)
• Molecular Docking Simulation
• Molecular Structure
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Parkinsonian Disorders (drug therapy, enzymology, pathology)
• Substantia Nigra (drug effects, enzymology, pathology)
• Tyrosine 3-Monooxygenase (metabolism)