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Synthesis, monoamine oxidase inhibitory activity and computational study of novel isoxazole derivatives as potential antiparkinson agents.
- Source :
-
Computational biology and chemistry [Comput Biol Chem] 2019 Apr; Vol. 79, pp. 63-72. Date of Electronic Publication: 2019 Jan 29. - Publication Year :
- 2019
-
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.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Antiparkinson Agents chemical synthesis
Antiparkinson Agents chemistry
Dose-Response Relationship, Drug
Humans
Isoxazoles chemical synthesis
Isoxazoles chemistry
Mice
Molecular Docking Simulation
Molecular Structure
Monoamine Oxidase Inhibitors chemical synthesis
Monoamine Oxidase Inhibitors chemistry
Motor Activity drug effects
Parkinson Disease metabolism
Structure-Activity Relationship
Antiparkinson Agents pharmacology
Computer Simulation
Isoxazoles pharmacology
Monoamine Oxidase metabolism
Monoamine Oxidase Inhibitors pharmacology
Parkinson Disease drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-928X
- Volume :
- 79
- Database :
- MEDLINE
- Journal :
- Computational biology and chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30731360
- Full Text :
- https://doi.org/10.1016/j.compbiolchem.2019.01.012