Indole-Substituted Benzothiazoles and Benzoxazoles as Selective and Reversible MAO-B Inhibitors for Treatment of Parkinson's Disease
- Authors
- Nam, Min-Ho; Park, Moosung; Park, Hyeri; Kim, Youngjae; Yoon, Seulki; Sawant, Vikram Shahaji; Cho, Ji Won; Park, Jong-Hyun; Park, Ki Duk; Min, Sun-Joon; Lee, C. Justin; Chooaii, Hyunah
- Issue Date
- Jul-2017
- Publisher
- American Chemical Society
- Keywords
- MAO-B; MAO-B inhibitor; Parkinson' s disease; benzothiazole; benzoxazole; MPTP-induced animal model
- Citation
- ACS Chemical Neuroscience, v.8, no.7, pp.1519 - 1529
- Indexed
- SCIE
SCOPUS
- Journal Title
- ACS Chemical Neuroscience
- Volume
- 8
- Number
- 7
- Start Page
- 1519
- End Page
- 1529
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/9480
- DOI
- 10.1021/acschemneuro.7b00050
- ISSN
- 1948-7193
- 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-IN-indol-5-yl)benzo[d]-thiazole with an IC50 value of 28 nM with no apparent effect on MAO-A activity at 10 mu M. 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 Sb 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.
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Collections - COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY > DEPARTMENT OF CHEMICAL AND MOLECULAR ENGINEERING > 1. Journal Articles
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