Neuroprotective effects of benzyloxy substituted small molecule monoamine oxidase B inhibitors in Parkinson’s disease |
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| Institution: | 1. Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai 201203, China;2. Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China;1. NTZ Lab Ltd., Krasno selo 198, Sofia 1618, Bulgaria;2. Department of Chemistry, University of Bielefeld, Universitätsstr. 25, 33615 Bielefeld, Germany;3. Bulgarian Academy of Sciences, Institute of Organic Chemistry, Centre of Phytochemistry, Acad. G. Bonchev Str., Bl. 9, Sofia 1113, Bulgaria;4. BioSolveIT GmbH, An der Ziegelei 79, 53757 St. Augustin, Germany;1. Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal Do Rio de Janeiro, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), CCS, Cidade Universitária, P.O. Box 68024, 21941-971, Rio de Janeiro, RJ, Brazil;2. Programa de Pós-graduação Em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, Brazil;3. Laboratório de Apoio Ao Desenvolvimento Tecnológico-LADETEC. Instituto de Química, Universidade Federal Do Rio de Janeiro, RJ, Brazil;4. Laboratório de Inflamação, Instituto Oswaldo Cruz-Fiocruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, 21045-900, Brazil;5. Programa de Pós-graduação Em Produtos Naturais e Sintéticos Bioativos, Centro de Ciências da Saúde, Universidade Federal da Paraíba, João Pessoa, Brazil;6. Departamento de Medicina, Campus Senador Helvídio Nunes de Barros, Universidade Federal Do Piauí, Picos, Brazil;7. Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal da Paraíba, João Pessoa, Brazil;8. Laboratório de Cristalografia Bioprocessos e Modelagem Molecular – LaBioCriMM. Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, AL, Brazil;1. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China;2. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China;3. School of Medicine, Henan University Minsheng College, Kaifeng 475000, China |
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| 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 of 13 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 that 13 is an effective and promising candidate to be further developed as disease-modifying drug for Parkinson’s disease therapy. |
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| Keywords: | Parkinson’s disease Monoamine oxidase BBB permeability Apoptosis Neuroprotection |
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