Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson’s disease
- Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson’s disease
- 박혜리; 김지윤; 김태근; 조선미; 염미영; 문봉진; 추일한; 이재익; 임은정; 박기덕; 민선준; 남길수; 금교창; 이창준; 추현아
- MAOB inhibitor; Parkinson's Disease; Monoamine oxidase B; MAO-B; Oxazolopyridine; Thiazolopyridine
- Issue Date
- Bioorganic & medicinal chemistry
- VOL 21, NO 17, 5480-5487
- 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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