Neuroprotective effects of benzyloxy substituted small molecule monoamine oxidase B inhibitors in Parkinson’s disease
Introduction
Parkinson’s disease (PD) is a degenerative disorder of the central nervous system (CNS) which characterized by a progressive loss of pigmented dopaminergic neurons in the substantia nigra pars compacta.1, 2 The cornerstone of PD therapy is aimed at enhancing central dopamine levels with its direct metabolic precursor, l-3,4-dihydroxyphenylalanine (l-DOPA).3 To enhance the therapeutic efficacy of l-DOPA and reduce the occurrence of dopamine-associated side effects, the drug is frequently administered in combination with the inhibitors that reduce the metabolism of dopamine, such as catechol-O-methyl transferase (COMT) and monoamine oxidase type B (MAO-B) inhibitors.4, 5 Thus, inhibition of MAO-B leads to enhancement of dopaminergic neurotransmission, which considered useful in the early PD therapy.6, 7
In the previous discovery of MAO-B inhibitors, propargylamine derivatives have been shown as selective and potent MAO-B inhibitory activities, and those compounds have been further examined neuroprotective capabilities against neurodegeneration by preventing apoptosis.8, 9, 10, 11, 12 Among them, selegiline and rasagiline were successfully approved by the U. S. FDA for the treatment of PD. Both selegiline and rasagiline are used in early PD as monotherapy and adjunctive therapy to levodopa and dopamine agonists in later stages of PD. However, the clinical trials were unsuccessful to shown a clear neuroprotective action, which led to the limited usage of selegiline and rasagiline as disease-modifying drugs.13 Therefore, the development of novel MAO-B inhibitors with potent inhibitory potency, definite therapeutic action and fewer side effects is still necessary. In fact, various benzyloxy substituted molecules as new type of excellent MAO-B inhibitors have been highly described by Petzer’s group and other researchers in recent years, such as acetophenones, indoles, quinolinones, coumarins, chromones, chromanones, a-tetralone and phthalide analogues.14, 15, 16, 17, 18, 19, 20, 21 Although these benzyloxy substituted small molecules have been identified as highly potent, selective, and irreversible MAO-B inhibitors, but their therapeutic potentials against Parkinson’s disease have not been investigated in detail. It is necessary to evaluate the neuroprotective activity and molecular mechanism of these derivatives in cells model.
For this purpose, we had synthesized a series of representative benzyloxy substituted compounds with different scaffolds (Fig. 1) and their MAO-A/B inhibitory activities had also been evaluated. In addition, these compounds were also tested for neuroprotective effects with PC12 cells model treated by 6-OHDA and rotenone, respectively. The neuroprotective effects of the preferred compounds against neurotoxins-induced apoptosis were confirmed with flow cytometry and staining method. To investigate drug-like properties, the blood–brain barrier (BBB) permeability, ADMET properties, and toxicity were also evaluated by in vitro and in vivo methods.
Section snippets
Chemistry
These representative benzyloxy substituted derivatives (1–31) were efficiently synthesized along with the pathway shown in Fig. 2. The starting materials (various skeletons, see Supporting information for the synthesis of key intermediates S1–4)17, 19, 21 reacted with the appropriate benzyl bromides in the presence of K2CO3 to give the target compounds in moderate to good yields.
Inhibition of MAOs
According to the reported assay with rasagiline and iproniazid22, 23, 24, the MAO inhibitory activities of compounds 1
Conclusions
In conclusion, this study showed that most of the representative benzyloxy substituted derivatives 5–8, 12–17, 25, 28 and 31 not only possessed selective and potent MAO-B inhibitory activities, but also exhibited neuroprotective properties in 6-OHDA- and rotenone-treated PC12 cells. Additionally, the selected compounds displayed no significant cytotoxicity, fine oral absorption and BBB permeability when evaluated for ADMET properties in silico. Moreover, the most promising compound 13 exhibited
Chemistry
All common reagents and solvents were obtained from commercial suppliers and used without further purification. Reaction progress was monitored using analytical thin layer chromatography (TLC) on precoated silica gel GF254 plates (Qingdao Haiyang Chemical Plant, Qingdao, China) plates and the spots were detected under UV light (254 nm). Column chromatography was performed on silica gel (90–150 μM; Qingdao Marine Chemical Inc.) Melting points were measured on an XT-4 micromelting point instrument
Acknowledgments
The research work was financially supported by the Project of National Natural Sciences Foundation of China (81573313), the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT-IRT_15R63), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
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These authors contributed equally.