Design, synthesis, molecular docking, and in vitro α-glucosidase inhibitory activities of novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines against yeast and rat α-glucosidase
Abstract:In an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing I… Show more
“…With the above-mentioned interactions, CD-59 was primarily bound with the domain A of the enzyme, within the inhibitor binding site. These binding interactions resembled the interactions reported in previous reports by Peytam et al (2021) [29] where 3-amino-2,4diarylbenzo [4,5] imidazo [1,2-a] pyrimidines were evaluated for their α-glucosidase (PDB ID: 3A4A) inhibitory activity (used AutoDock Tools 1.5.6 for docking). Additionally, the penetration of the CD-59 into the inhibitor binding site leads to the formation of more binding interactions in comparison with Shukla et al (2021) [30], who evaluated glycosyl-1, 2, 3-1H-triazolyl methyl benzamide derivatives as the α-glucosidase (PDB ID: 3A4A) inhibitors (used Schrodinger Glide module for docking).…”
Coumarin derivatives are proven for their therapeutic uses in several human diseases and disorders such as inflammation, neurodegenerative disorders, cancer, fertility, and microbial infections. Coumarin derivatives and coumarin-based scaffolds gained renewed attention for treating diabetes mellitus. The current decade witnessed the inhibiting potential of coumarin derivatives and coumarin-based scaffolds against α-glucosidase and α-amylase for the management of postprandial hyperglycemia. Hyperglycemia is a condition where an excessive amount of glucose circulates in the bloodstream. It occurs when the body lacks enough insulin or is unable to correctly utilize it. With open-source and free in silico tools, we have investigated novel 80 coumarin derivatives for their inhibitory potential against α-glucosidase and α-amylase and identified a coumarin derivative, CD-59, as a potential dual inhibitor. The ligand-based 3D pharmacophore detection and search is utilized to discover diverse coumarin-like compounds and new chemical scaffolds for the dual inhibition of α-glucosidase and α-amylase. In this regard, four novel coumarin-like compounds from the ZINC database have been discovered as the potential dual inhibitors of α-glucosidase and α-amylase (ZINC02789441 and ZINC40949448 with scaffold thiophenyl chromene carboxamide, ZINC13496808 with triazino indol thio phenylacetamide, and ZINC09781623 with chromenyl thiazole). To summarize, we propose that a coumarin derivative, CD-59, and ZINC02789441 from the ZINC database will serve as potential lead molecules with dual inhibition activity against α-glucosidase and α-amylase, thereby discovering new drugs for the effective management of postprandial hyperglycemia. From the reported scaffold, the synthesis of several novel compounds can also be performed, which can be used for drug discovery.
“…With the above-mentioned interactions, CD-59 was primarily bound with the domain A of the enzyme, within the inhibitor binding site. These binding interactions resembled the interactions reported in previous reports by Peytam et al (2021) [29] where 3-amino-2,4diarylbenzo [4,5] imidazo [1,2-a] pyrimidines were evaluated for their α-glucosidase (PDB ID: 3A4A) inhibitory activity (used AutoDock Tools 1.5.6 for docking). Additionally, the penetration of the CD-59 into the inhibitor binding site leads to the formation of more binding interactions in comparison with Shukla et al (2021) [30], who evaluated glycosyl-1, 2, 3-1H-triazolyl methyl benzamide derivatives as the α-glucosidase (PDB ID: 3A4A) inhibitors (used Schrodinger Glide module for docking).…”
Coumarin derivatives are proven for their therapeutic uses in several human diseases and disorders such as inflammation, neurodegenerative disorders, cancer, fertility, and microbial infections. Coumarin derivatives and coumarin-based scaffolds gained renewed attention for treating diabetes mellitus. The current decade witnessed the inhibiting potential of coumarin derivatives and coumarin-based scaffolds against α-glucosidase and α-amylase for the management of postprandial hyperglycemia. Hyperglycemia is a condition where an excessive amount of glucose circulates in the bloodstream. It occurs when the body lacks enough insulin or is unable to correctly utilize it. With open-source and free in silico tools, we have investigated novel 80 coumarin derivatives for their inhibitory potential against α-glucosidase and α-amylase and identified a coumarin derivative, CD-59, as a potential dual inhibitor. The ligand-based 3D pharmacophore detection and search is utilized to discover diverse coumarin-like compounds and new chemical scaffolds for the dual inhibition of α-glucosidase and α-amylase. In this regard, four novel coumarin-like compounds from the ZINC database have been discovered as the potential dual inhibitors of α-glucosidase and α-amylase (ZINC02789441 and ZINC40949448 with scaffold thiophenyl chromene carboxamide, ZINC13496808 with triazino indol thio phenylacetamide, and ZINC09781623 with chromenyl thiazole). To summarize, we propose that a coumarin derivative, CD-59, and ZINC02789441 from the ZINC database will serve as potential lead molecules with dual inhibition activity against α-glucosidase and α-amylase, thereby discovering new drugs for the effective management of postprandial hyperglycemia. From the reported scaffold, the synthesis of several novel compounds can also be performed, which can be used for drug discovery.
“…Compound G5 is found to be highly safe owing to having no toxicity behavior. Although toxicity radar exhibited that no compound is active against other parameters depicted mainly by orange line as immunotoxicity, mutagenicity, ATPase family AAA domain-containing protein 5 (ATAD5), Phosphoprotein (p53), Heat shock response element (HSE), nuclear factor-like 2/antioxidant responsive element (nrf2/ARE), peroxisome proliferate activated receptor gamma (PPAR-Gamma), estrogen receptor ligand binding domain (ER-LBD), estrogen receptor alpha (ER), aromatase, androgen receptor (AR), aryl hydrocarbon receptor ( Peytam et al, 2021 ), androgen receptor ligand binding domain (AR-LBD) and cytotoxicity ( Nnadi, Ozioko, Eneje, Onah, & Obonga, 2020 ). Fig.…”
“…Diabetes mellitus is a progressive metabolic disease characterized by in ability of the body to control blood sugar levels resulting in chronic hyperglycemia ( 23 ). Several traditional medications for the treatment of type 2 diabetes increases the insulin action and its secretion for β-pancreatic cells ( 24 ).…”
In an attempt to find new targets for α-amylase and α-glucosidase for the treatment of type 2 diabetes mellitus, the present study aims in determining the anti-diabetic potential of synthesized dihydropyrimidinone derivatives. The in vitro α-glucosidase and α-amylase inhibitory activity was performed and the molecular docking analysis of the ligand in the active binding site of target protein was determined. The results revealed significant percent inhibition of α-glucosidase by the compound 6-benzyl-4-(4-hydroxyphenyl)-3,4,6,7-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-2,5-dione (compound A). The active compound showed 81.99% inhibition when compared to standard ascorbic acid having percent inhibition 81.18%. The IC50 of active compound (A) showed to be 1.02 µg/ml. The molecular docking analysis revealed that the ligand bound to the active binding site of protein with the lowest binding energy of -7.9 kcal/mol that was also significantly similar to standard having -7.8 kcal/mol binding energy. The molecular dynamic simulation studies also revealed stable binding of ligand in the active binding site of protein with low RMSD of 1.7 Å similar to the protein RMSD 1.6Å In conclusion, the study revealed a potential new target against α-glucosidase to treat type 2 diabetes mellitus.
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