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 IC 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.

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Parkinson's disease (PD) is a central nervous system disorder accompanied by tremor, slow movement, motor impairment, and dementia. 1,2 These symptoms of PD mainly result from the death of dopaminergic neurons in substantia nigra (SN) and the deficiency of dopamine inside the brain. 3 Dopamine is a type of monoamine neurotransmitter and acts as a chemical messenger to regulate neuronal signaling in brain, thereby controls motor functions. 4 Levodopa (L-dopa) is the major treatment for PD and exerts its effect as a dopamine precursor. 5 However, doparesistance or serious complications are observed after an initial period of treatment. 6 Besides L-dopa treatment, another therapeutic way to restore dopamine function is the suppression of dopamine catabolism. Monoamine oxidase (MAO) is involved in down-regulation of dopamine level which catalyzes the deamination and degradation of dopamine. 7 Inhibition of MAO blocks the breakdown of dopamine, thereby prolongs the action of dopamine in the brain. 8 There are two isoforms of MAO-A and MAO-B. Although they share about 70% of structure similarity, MAO-A and -B exhibit different substrate specificity as well as diverse regional distribution in brain tissue. 9 MAO-B has been regarded as a therapeutic target for PD in clinic because the elevated activity of MAO-B was observed in the SN of PD patients. 10