Exploring the Dual Inhibitory Activity of Novel Anthranilic Acid Derivatives towards α-Glucosidase and Glycogen Phosphorylase Antidiabetic Targets: Design, In Vitro Enzyme Assay, and Docking Studies
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Screening
2.2.1. α-Glucosidase Inhibitory Assay
2.2.2. Glycogen Phosphorylase Inhibitory Assay
2.2.3. In Vivo Antidiabetic Screening
2.3. Molecular Docking Studies and SAR Analyses
3. Materials and Methods
3.1. Chemistry
3.2. Synthesis and Characterization of Methyl 2-(Picolinamido)benzoate (1)
3.3. General Procedure for the Synthesis of Diamides 3a–e and 5a–c
3.4. Synthesis and Characterization of N-(2-(Hydrazinecarbonyl)phenyl)picolinamide (6)
3.5. General Procedure for the Synthesis of Schiff Bases-Type Hydrazones 7a–d
3.6. α-Glucosidase Inhibition Assay
3.7. Glycogen Phosphorylase Enzyme Assay
3.8. In Vivo Antidiabetic Screening
3.9. Molecular Docking
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are currently not available from the authors. |
Compounds | IC50 (µM) | Scaffold | |
---|---|---|---|
α-Glucosidase | Glycogen Phosphorylase | ||
1 | 0.7355 ± 2.4 | 0.5415 ± 0.06 | N-Furoylanthranilate (NFA) |
3a | 0.0896 ± 1.52 | 0.1502 ± 0.07 | Benzyl NFA |
3b | 0.0223 ± 0.08 | 0.01808 ± 0.84 | |
3c | 0.0585 ± 7.57 | 0.08639 ± 0.02 | |
3d | 0.0947 ± 0.68 | 0.1774 ± 0.05 | |
3e | 0.0708 ± 14.2 | 0.262 ± 0.01 | |
5a | 0.0477 ± 0.59 | 0.07047 ± 0,01 | Sulfonamide NFA |
5b | 0.0212 ± 0.07 | 0.0166 ± 0.09 | |
5c | 0.01247 ± 0.01 | 0.02291 ± 0.57 | |
6 | 0.4166 ± 11.4 | 0.5818 ± 0.58 | NFA-Hydrazine |
7a | 0.0445 ± 12.1 | 0.2078 ± 2.57 | Benzylidine NFA |
7b | 0.0176 ± 0.09 | 0.01372 ± 0.03 | |
7d | 0.07842 ± .05 | 0.054 ± 5.14 | |
7c | 0.2313 ± 0.57 | 0.0367 ± 2.56 | |
1-Deoxynojirimycin | 0.01011 ± 1.81 | 0.0556 ± 0.11 | - |
Groups | Blood Glucose Level (mg/dL) | ||
---|---|---|---|
Fasting | Reading 1 | Reading 2 | |
Control | 72 ± 1.72 | 147 ± 0.88 | 140 ± 3.17 |
Diabetic | 209 ± 0.66 | 172 ± 2.72 | 176 ± 2.90 |
Acarbose | 204 ± 4.5 | 147 ± 2.0 | 136 ± 3.28 |
7b | 207 ± 0.88 | 120 ± 0.88 | 116 ± 0.57 |
Compounds | Fragment | Target Residues (Distance, Å) | Interaction | Binding Energy (dG) |
---|---|---|---|---|
5b | C=O (anthranilate) | Gln71 (3.14) | H-bonding | −14.5 |
Phenyl (sulphonamide) | Tyr75, Gln71, Gln72 | Hydrophobic | ||
Pyridine | Arg193 (3.08) | H-bonding | ||
Ile68 | Hydrophobic | |||
Phenyl (anthranilate) | Ala313 | Aromatic stacking | ||
7b | –OH | Asp76 (3.1) | H-bonding | −15.4 |
–OH | Tyr738 (4.65) | H-bonding | ||
C=O (anthranilate) | Gln71 (3.05) | H-bonding | ||
Pyridine | Phe196 | Hydrophobic | ||
Phenyl (anthranilate) | Ile68 | Hydrophobic | ||
GSK254 | Carboxylic gp. | Arg310 (2.89) | H-bonding | −13.5 |
Phenyl (anthranilate) | Ile68 | Hydrophobic | ||
Carbonyl linker | Gln71 (3.08) | H-bonding |
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Ihmaid, S. Exploring the Dual Inhibitory Activity of Novel Anthranilic Acid Derivatives towards α-Glucosidase and Glycogen Phosphorylase Antidiabetic Targets: Design, In Vitro Enzyme Assay, and Docking Studies. Molecules 2018, 23, 1304. https://doi.org/10.3390/molecules23061304
Ihmaid S. Exploring the Dual Inhibitory Activity of Novel Anthranilic Acid Derivatives towards α-Glucosidase and Glycogen Phosphorylase Antidiabetic Targets: Design, In Vitro Enzyme Assay, and Docking Studies. Molecules. 2018; 23(6):1304. https://doi.org/10.3390/molecules23061304
Chicago/Turabian StyleIhmaid, Saleh. 2018. "Exploring the Dual Inhibitory Activity of Novel Anthranilic Acid Derivatives towards α-Glucosidase and Glycogen Phosphorylase Antidiabetic Targets: Design, In Vitro Enzyme Assay, and Docking Studies" Molecules 23, no. 6: 1304. https://doi.org/10.3390/molecules23061304