Synthesis,monoamine oxidase inhibitory activity and computational study of novel isoxazole derivatives as potential antiparkinson agents |
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| Institution: | 1. Pharmaceutical Technology Transfer Center, Yaroslavl State Pedagogical University named after K.D. Ushinsky, 108 Respublikanskaya St., Yaroslavl, Russian Federation;2. Yaroslavl State Technical University, 88 Moskovskii av., Yaroslavl, Russian Federation;3. Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa;4. A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov St. 28, Moscow 119991, Russian Federation;5. G.V. Plekhanov Russian University of Economics, Stremyanny per. 36, Moscow 117997, Russian Federation;1. Pharmaceutical Technology Transfer Center, Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl 150000, Russian Federation;2. Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof, Saint Petersburg 198504, Russian Federation;3. Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation;4. Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa;1. Facultad de Ciencias, Instituto de Química, Pontificia Universidad Católica de Valparaíso, Av. Universidad #330, Curauma, Valparaíso, Chile;2. Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Bretaña 1111, Valparaíso, Chile;3. Departamento de Química, Universidad Técnico Federico Santa María, Av. España 1680, Valparaíso, Chile;4. Chronic Diseases Pharmacology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;5. Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain;6. Departamento de Química Orgánica, Facultade de Farmacia, Universidade Santiago de Compostela, 15782 Santiago de Compostela, Spain;7. Instituto de Ciencias Químicas Aplicadas, Universidad Autónoma de Chile, 7500912 Santiago, Chile;8. CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal |
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| Abstract: | Monoamine oxidase (MAO) enzymes are one of the most promising targets for the treatment of neurological disorders. A series of phenylisoxazole carbohydrazides was designed, synthesized and screened for both MAO-A and MAO-B inhibition using Amplex Red assays. None of the compounds inhibited the MAO-A activity while most of them significantly inhibited MAO-B in the micromolar to nanomolar range. Among them, the compound N'-(4-methylbenzylidene)-5-phenylisoxazole-3-carbohydrazide (6c) exhibited the most potent inhibitory activity towards MAO-B. Enzyme kinetic studies revealed the reversible and competitive nature of compound 6c towards MAO-B inhibition. The results of the enzyme inhibition assay were in agreement with molecular docking study, in which compound 6c displayed a strong binding affinity for MAO-B with a docking score of -10.98 Kcal/mol. In order to explore the neuroprotective effect of compound 6c, MPTP-induced mouse model for Parkinson’s disease was used, and motor behavioural assessment of experimental animals was carried out. The compound 6c was able to significantly prevent the MPTP-induced neurotoxicity as revealed by improvement in gait behaviour in footprint test and increase in grip strength score in horizontal wire test. Thus, phenylisoxazole carbohydrazides can be promising leads in the development of potent, selective and reversible MAO-B inhibitors for the treatment of Parkinson’s disease. |
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| Keywords: | Isoxazole Carbohydrazide Parkinson’s disease MAO inhibitor Neurodegenerative diseases |
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