Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson’s disease |
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Authors: | Hye Ri Park Jiyoon Kim Taekeun Kim Seonmi Jo Miyoung Yeom Bongjin Moon Il Han Choo Jaeick Lee Eun Jeong Lim Ki Duk Park Sun-Joon Min Ghilsoo Nam Gyochang Keum C Justin Lee Hyunah Choo |
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Institution: | 1. Center for Neuro-Medicine, Korea Institute of Science and Technology, Hwarangro 14-gil-5, Seongbuk-gu, Seoul 136-791, Republic of Korea;2. Department of Chemistry, Sogang University, Mapo-gu, Seoul 121-742, Republic of Korea;3. Center for Functional Connectomics, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea;4. Department of Neuropsychiatry, School of Medicine, Chosun University, Pilmoondaero 309, Dong-gu, Kwangju 501-759, Republic of Korea;5. Doping Control Center, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea;6. Center for Neural Science, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Republic of Korea |
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Abstract: | In Parkinson’s disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson’s disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson’s disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure–activity relationship study revealed that the piperidino group was the best choice for the R1 amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5 nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5 nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives. |
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Keywords: | Monoamine oxidase B MAO-B Parkinson’s disease Oxazolopyridine Thiazolopyridine |
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