Format

Send to

Choose Destination
ACS Chem Neurosci. 2017 Jul 19;8(7):1519-1529. doi: 10.1021/acschemneuro.7b00050. Epub 2017 Mar 30.

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

Nam MH1,2, Park M3,4, Park H3, Kim Y3,5, Yoon S3,4, Sawant VS3,4, Choi JW3,6, Park JH3, Park KD3,4, Min SJ7, Lee CJ1,8, Choo H3,4.

Author information

1
Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
2
Department of Science in Korean Medicine, Graduate School, Kyung Hee University , Kyungheedaero 26, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
3
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
4
Department of Biological Chemistry, Korea University of Science and Technology , Youseong-gu, Daejeon 34113, Korea.
5
Department of Chemistry, Yonsei University , Seodaemun-gu, Seoul 03722, Republic of Korea.
6
Department of Biotechnology, Yonsei University , 50, Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
7
Department of Applied Chemistry, Hanyang University , Ansan, Gyeonggi-du 15588, Korea , and.
8
KU-KIST School of Converging Science and Technology, Korea University , Seoul 02841, Korea.

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.

KEYWORDS:

MAO-B; MAO-B inhibitor; MPTP-induced animal model; Parkinson’s disease; benzothiazole; benzoxazole

PMID:
28332824
DOI:
10.1021/acschemneuro.7b00050
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center