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

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, Changjoon Lee, Hyunah Choo

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19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1519-1529
Number of pages11
JournalACS Chemical Neuroscience
Volume8
Issue number7
DOIs
Publication statusPublished - 2017 Jul 19

Keywords

  • benzothiazole
  • benzoxazole
  • MAO-B
  • MAO-B inhibitor
  • MPTP-induced animal model
  • Parkinson's disease

ASJC Scopus subject areas

  • Physiology
  • Biochemistry
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Nam, M. H., Park, M., Park, H., Kim, Y., Yoon, S., Sawant, V. S., Choi, J. W., Park, J. H., Park, K. D., Min, S. J., Lee, C., & Choo, H. (2017). Indole-Substituted Benzothiazoles and Benzoxazoles as Selective and Reversible MAO-B Inhibitors for Treatment of Parkinson's Disease. ACS Chemical Neuroscience, 8(7), 1519-1529. https://doi.org/10.1021/acschemneuro.7b00050