1. New phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamides as dual inhibitors against α-glucosidase and PTP-1B for the treatment of type 2 diabetes.
- Author
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Ansariashlaghi S, Fakhrioliaei A, Mohammadi-Khanaposhtani M, Noori M, Asadi M, Mojtabavi S, Faramarzi MA, Esfahani EN, Rastegar H, Larijani B, Azizian H, and Mahdavi M
- Subjects
- Structure-Activity Relationship, Humans, Molecular Structure, Triazoles pharmacology, Triazoles chemistry, Triazoles chemical synthesis, Dose-Response Relationship, Drug, Semicarbazides pharmacology, Semicarbazides chemistry, Semicarbazides chemical synthesis, Diabetes Mellitus, Type 2 drug therapy, Glycoside Hydrolase Inhibitors pharmacology, Glycoside Hydrolase Inhibitors chemical synthesis, Glycoside Hydrolase Inhibitors chemistry, Protein Tyrosine Phosphatase, Non-Receptor Type 1 antagonists & inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 1 metabolism, Molecular Docking Simulation, alpha-Glucosidases metabolism, Hypoglycemic Agents pharmacology, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents chemistry
- Abstract
This study describes the design, synthesis, and evaluation of a novel series of phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives (7a-l) as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1-B (PTB-1B). The latter enzymes are two important targets in the treatment of type 2 diabetes. The in vitro obtained data demonstrated that all title compounds 7a-l were more potent than the standard inhibitor acarbose against α-glucosidase while only four derivatives (7a, 7g, 7h, and 7h) were more potent than the standard inhibitor suramin against PTP-1B. Furthermore, these data showed that the most potent α-glucosidase inhibitor was compound 7i, with sixfold higher inhibitory activity than acarbose, and the most potent PTP-1B inhibitor was compound 7a with 3.5-fold higher inhibitory activity than suramin. Kinetic studies of compounds 7i and 7a revealed that they inhibited their target enzymes in a competitive mode. The docking study demonstrated that compounds 7i and 7a well occupied the active site pockets of α-glucosidase and PTP-1B, respectively. In silico pharmacokinetic and toxicity assays of the most potent compounds were performed, and the obtained results were compared with those of the standard inhibitors., (© 2024 Deutsche Pharmazeutische Gesellschaft.)
- Published
- 2024
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