Exploring fluorine-substituted piperidines as potential therapeutics for diabetes mellitus and Alzheimer's diseases.
Eur J Med Chem
; 273: 116523, 2024 Jul 05.
Article
in En
| MEDLINE
| ID: mdl-38795518
ABSTRACT
In the current study, a series of fluorine-substituted piperidine derivatives (1-8) has been synthesized and characterized by various spectroscopic techniques. In vitro and in vivo enzyme inhibitory studies were conducted to elucidate the efficacy of these compounds, shedding light on their potential therapeutic applications. To the best of our knowledge, for the first time, these heterocyclic structures have been investigated against α-glucosidase and cholinesterase enzymes. The antioxidant activity of the synthesized compounds was also assessed. Evaluation of synthesized compounds revealed notable inhibitory effects on α-glucosidase and cholinesterases. Remarkably, the target compounds (1-8) exhibited extraordinary α-glucosidase inhibitory activity as compared to the standard acarbose by several-fold. Subsequently, the potential antidiabetic effects of compounds 2, 4, 5, and 6 were validated using a STZ-induced diabetic rat model. Kinetic studies were also performed to understand the mechanism of inhibition, while structure-activity relationship analyses provided valuable insights into the structural features governing enzyme inhibition. Kinetic investigations revealed that compound 4 displayed a competitive mode of inhibition against α-glucosidase, whereas compound 2 demonstrated mixed-type behavior against AChE. To delve deeper into the binding interactions between the synthesized compounds and their respective enzyme targets, molecular docking studies were conducted. Overall, our findings highlight the promising potential of these densely substituted piperidines as multifunctional agents for the treatment of diseases associated with dysregulated glucose metabolism and cholinergic dysfunction.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperidines
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Cholinesterase Inhibitors
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Diabetes Mellitus, Experimental
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Alpha-Glucosidases
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Alzheimer Disease
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Molecular Docking Simulation
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Glycoside Hydrolase Inhibitors
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Fluorine
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Hypoglycemic Agents
Language:
En
Journal:
Eur J Med Chem
Year:
2024
Document type:
Article