Indole-Substituted Benzothiazoles and Benzoxazoles as Selective and Reversible MAO-B Inhibitors for Treatment of Parkinson's Disease.
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 IC50value 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.
Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|Department of Science in Korean Medicine, Graduate School, Kyung Hee University , Kyungheedaero 26, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
Min-Ho
0000-0002-6191-1268
MH
Nam
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology , Youseong-gu, Daejeon 34113, Korea.
Moosung
M
Park
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
Hyeri
H
Park
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|Department of Chemistry, Yonsei University , Seodaemun-gu, Seoul 03722, Republic of Korea.
Youngjae
Y
Kim
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology , Youseong-gu, Daejeon 34113, Korea.
Seulki
S
Yoon
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology , Youseong-gu, Daejeon 34113, Korea.
Vikram Shahaji
VS
Sawant
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|Department of Biotechnology, Yonsei University , 50, Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Ji Won
JW
Choi
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
Jong-Hyun
JH
Park
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology , Youseong-gu, Daejeon 34113, Korea.
Ki Duk
KD
Park
Department of Applied Chemistry, Hanyang University , Ansan, Gyeonggi-du 15588, Korea , and.
Sun-Joon
0000-0003-0867-4416
SJ
Min
Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|KU-KIST School of Converging Science and Technology, Korea University , Seoul 02841, Korea.
C Justin
CJ
Lee
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology , Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology , Youseong-gu, Daejeon 34113, Korea.
Hyunah
H
Choo
D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000978:Antiparkinson Agents; D052160:Benzothiazoles; D001583:Benzoxazoles; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase
MAO-B; MAO-B inhibitor; MPTP-induced animal model; Parkinson’s disease; benzothiazole; benzoxazole