Neuroprotective effects of benzyloxy substituted small molecule monoamine oxidase B inhibitors in Parkinson's disease. Issue 22 (15th November 2016)

• Record Type: Journal Article
• Authors: Wang, Zhimin; Wu, Jiajia; Yang, Xuelian; Cai, Pei; Liu, Qiaohong; Wang, Kelvin D.G.; Kong, Lingyi; Wang, Xiaobing
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 22(2016)
• Page Start: 5929
• Page End: 5940
• Publication Date: 2016-11-15
• Subjects: Parkinson's disease -- Monoamine oxidase -- BBB permeability -- Apoptosis -- Neuroprotection; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.09.050
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A series of representative benzyloxy substituted MAO-B inhibitors were synthesized and evaluated. Compounds5 –8, 12 –17, 25, 28 and31 exhibited neuroprotective effects against 6-OHDA- and rotenone-treated PC12 cells. Compound13 showed neuroprotective effects against neurotoxins-induced ROS accumulation and apoptosis. Compound13 might be promising candidates for the therapy of Parkinson's disease. Abstract: The benzyloxy substituted small molecules are well-known highly potent monoamine oxidase B inhibitors, but their therapeutic potential against Parkinson's disease have not been investigated in detail. In this paper, a series of representative benzyloxy substituted derivatives were synthesized and evaluated for MAO-A/B inhibition. In addition, their neuroprotective effects were investigated in 6-OHDA- and rotenone-treated PC12 cells. It was observed that most of the compounds exhibited a marked increase in survival of PC12 cells which treated with the neurotoxins. Among them, 13 exhibited remarkable and balanced neuroprotective potency. The protective effects of13 against neurotoxins-induced apoptosis were confirmed with flow cytometry and staining methods. Furthermore, 13 also showed good BBB permeability and low toxicity according to in vitro BBB prediction and in vivo acute toxicity test. The results indicated that13 is an effective and promising candidate to be further developed as disease-modifying drug for Parkinson's disease therapy.