Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches
In the development of novel antidiabetic agents, a novel series of isoxazolidine-isatin hybrids were designed, synthesized, and evaluated as dual α‐amylase and α-glucosidase inhibitors. The precise structures of the synthesized scaffolds were characterized using different spectroscopic techniques an...
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Elsevier
2024-02-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S240584402401942X |
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| author | Siwar Ghannay Budur Saleh Aldhafeeri Iqrar Ahmad Abuzar E.A.E. Albadri Harun Patel Adel Kadri Kaiss Aouadi |
| author_facet | Siwar Ghannay Budur Saleh Aldhafeeri Iqrar Ahmad Abuzar E.A.E. Albadri Harun Patel Adel Kadri Kaiss Aouadi |
| author_sort | Siwar Ghannay |
| collection | DOAJ |
| description | In the development of novel antidiabetic agents, a novel series of isoxazolidine-isatin hybrids were designed, synthesized, and evaluated as dual α‐amylase and α-glucosidase inhibitors. The precise structures of the synthesized scaffolds were characterized using different spectroscopic techniques and elemental analysis. The obtained results were compared to those of the reference drug, acarbose (IC50 = 296.6 ± 0.825 μM for α‐amylase & IC50 = 780.4 ± 0.346 μM for α-glucosidase). Among the title compounds, 5d exhibited impressive α-amylase and α-glucosidase inhibitory activity with IC50 values of 30.39 ± 1.52 μM and 65.1 ± 3.11 μM, respectively, followed by 5h (IC50 = 46.65 ± 2.3 μM; IC50 = 85.16 ± 4.25 μM) and 5f (IC50 = 55.71 ± 2.78 μM; IC50 = 106.77 ± 5.31 μM). Mechanistic studies revealed that the most potent derivative 5d bearing the chloro substituent attached to the oxoindolin-3-ylidene core, and acarbose, are a competitive inhibitors of α-amylase and α-glucosidase, respectively. Structure activity relationship (SAR) was examined to guide further structural optimization of the most appropriate substituent(s). Moreover, drug-likeness qualities and ADMET prediction of the most active analogue, 5d was also performed. Subsequently, 5d was subjected to molecular docking and dynamic simulation during the progression of 120 ns analysis to check the essential ligand-receptor patterns, and to estimate its stability. In silico studies were found in good agreement with the in vitro enzymatic inhibitions results. In conclusion, we demonstrated that most potent compound 5d could be exploited as dual potential inhibitor of α-amylase and α-glucosidase for possible management of diabetes. |
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| language | English |
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| series | Heliyon |
| spelling | doaj.art-856612864df54719ab96211353e9e49d2024-03-09T09:26:32ZengElsevierHeliyon2405-84402024-02-01104e25911Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approachesSiwar Ghannay0Budur Saleh Aldhafeeri1Iqrar Ahmad2Abuzar E.A.E. Albadri3Harun Patel4Adel Kadri5Kaiss Aouadi6Department of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi ArabiaDepartment of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi ArabiaDivision of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, 425405, Maharashtra, IndiaDepartment of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi ArabiaDivision of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, 425405, Maharashtra, IndiaFaculty of Science and Arts in Baljurashi, Al-Baha University, P.O. Box (1988), Al-Baha, 65527, Saudi Arabia; Faculty of Science of Sfax, Department of Chemistry, University of Sfax, B.P. 1171, 3000, Sfax, Tunisia; Corresponding author. Faculty of Science and Arts in Baljurashi, Al-Baha University, P.O. Box (1988), Al-Baha, 65527, Saudi Arabia.Department of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi Arabia; Department of Chemistry, Laboratory of Heterocyclic Chemistry Natural Product and Reactivity/CHPNR, Faculty of Science of Monastir, University of Monastir, Avenue of the Environment, Monastir, 5019, Tunisia; Corresponding author. Department of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi Arabia.In the development of novel antidiabetic agents, a novel series of isoxazolidine-isatin hybrids were designed, synthesized, and evaluated as dual α‐amylase and α-glucosidase inhibitors. The precise structures of the synthesized scaffolds were characterized using different spectroscopic techniques and elemental analysis. The obtained results were compared to those of the reference drug, acarbose (IC50 = 296.6 ± 0.825 μM for α‐amylase & IC50 = 780.4 ± 0.346 μM for α-glucosidase). Among the title compounds, 5d exhibited impressive α-amylase and α-glucosidase inhibitory activity with IC50 values of 30.39 ± 1.52 μM and 65.1 ± 3.11 μM, respectively, followed by 5h (IC50 = 46.65 ± 2.3 μM; IC50 = 85.16 ± 4.25 μM) and 5f (IC50 = 55.71 ± 2.78 μM; IC50 = 106.77 ± 5.31 μM). Mechanistic studies revealed that the most potent derivative 5d bearing the chloro substituent attached to the oxoindolin-3-ylidene core, and acarbose, are a competitive inhibitors of α-amylase and α-glucosidase, respectively. Structure activity relationship (SAR) was examined to guide further structural optimization of the most appropriate substituent(s). Moreover, drug-likeness qualities and ADMET prediction of the most active analogue, 5d was also performed. Subsequently, 5d was subjected to molecular docking and dynamic simulation during the progression of 120 ns analysis to check the essential ligand-receptor patterns, and to estimate its stability. In silico studies were found in good agreement with the in vitro enzymatic inhibitions results. In conclusion, we demonstrated that most potent compound 5d could be exploited as dual potential inhibitor of α-amylase and α-glucosidase for possible management of diabetes.http://www.sciencedirect.com/science/article/pii/S240584402401942XDiabetesAntidiabetic agentsIsoxazolidine-isatin hybridsKinetic studyDrug-likenessMolecular docking and dynamics simulation |
| spellingShingle | Siwar Ghannay Budur Saleh Aldhafeeri Iqrar Ahmad Abuzar E.A.E. Albadri Harun Patel Adel Kadri Kaiss Aouadi Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches Heliyon Diabetes Antidiabetic agents Isoxazolidine-isatin hybrids Kinetic study Drug-likeness Molecular docking and dynamics simulation |
| title | Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches |
| title_full | Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches |
| title_fullStr | Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches |
| title_full_unstemmed | Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches |
| title_short | Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches |
| title_sort | identification of dual target isoxazolidine isatin hybrids with antidiabetic potential design synthesis in vitro and multiscale molecular modeling approaches |
| topic | Diabetes Antidiabetic agents Isoxazolidine-isatin hybrids Kinetic study Drug-likeness Molecular docking and dynamics simulation |
| url | http://www.sciencedirect.com/science/article/pii/S240584402401942X |
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