Design, synthesis, biological evaluation, kinetic studies and molecular modeling of imidazo-isoxazole derivatives targeting both α-amylase and α-glucosidase inhibitors
Herein, a novel set of imidazo-isoxazole derivatives containing thiourea and urea scaffolds were synthesized, characterized (1H NMR, 13C NMR, and elemental analysis). These compounds were biologically evaluated for their α-amylase and α-glucosidase inhibitory activity, identifying 5f as the most act...
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Elsevier
2024-10-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024144076 |
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| author | Etab AlRashidi Siwar Ghannay Abuzar E.A.E. Albadri Majdi Abid Adel Kadri Kaiss Aouadi |
| author_facet | Etab AlRashidi Siwar Ghannay Abuzar E.A.E. Albadri Majdi Abid Adel Kadri Kaiss Aouadi |
| author_sort | Etab AlRashidi |
| collection | DOAJ |
| description | Herein, a novel set of imidazo-isoxazole derivatives containing thiourea and urea scaffolds were synthesized, characterized (1H NMR, 13C NMR, and elemental analysis). These compounds were biologically evaluated for their α-amylase and α-glucosidase inhibitory activity, identifying 5f as the most active (IC50 26.67 ± 1.25 μM and 39.12 ± 1.83 μM against α-amylase α-glucosidase, respectively), better than the standard, acarbose. Enzymatic kinetic results showed that 5f and acarbose complete competitive type inhibitors. The structure-activity relationship (SAR) demonstrated that undergoing substitutions on R1 and R2 groups attached to the thiourea/urea moiety chains controlled the activity. Besides, in-silico ADMET study showed that almost title compounds exhibited satisfactory pharmacokinetic properties. In molecular docking study, the top performing compound (5f) exhibited higher binding energies (−5.501 and −6.414 kcal/mol, respectively) showing crucial interactions and that snuggly fit in their active site. To shed light on their mechanism of action, molecular dynamic (MD) simulations approach executed at 100 ns duration authenticated the high stability of 5f-1B2Y and 5f-3A4A complexes. The results of this investigation disclosed that compound 5f may serve as a potential lead, accomplished with in vivo studies, for the management of diabetes. |
| format | Article |
| id | doaj-art-b7b4be9bae6e44568334ef0a4a3efb58 |
| institution | OA Journals |
| issn | 2405-8440 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-b7b4be9bae6e44568334ef0a4a3efb582025-08-20T02:14:03ZengElsevierHeliyon2405-84402024-10-011020e3837610.1016/j.heliyon.2024.e38376Design, synthesis, biological evaluation, kinetic studies and molecular modeling of imidazo-isoxazole derivatives targeting both α-amylase and α-glucosidase inhibitorsEtab AlRashidi0Siwar Ghannay1Abuzar E.A.E. Albadri2Majdi Abid3Adel Kadri4Kaiss Aouadi5Department of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi ArabiaDepartment of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi ArabiaDepartment of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi ArabiaDepartment of Chemistry, College of Science, Jouf University, P.O. Box 2014, Sakaka, Aljouf, Kingdom of Saudi ArabiaDepartment of Chemistry, Faculty of Science, Al-Baha University, Al-Baha, 65431, Kingdom of Saudi Arabia; Faculty of Science of Sfax, Department of Chemistry, University of Sfax, B.P. 1171, 3000, Sfax, Tunisia; Corresponding author. Department of Chemistry, Faculty of Science, Al-Baha University, Al-Baha, 65431, Kingdom of Saudi Arabia.Department of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi Arabia; Corresponding author.Herein, a novel set of imidazo-isoxazole derivatives containing thiourea and urea scaffolds were synthesized, characterized (1H NMR, 13C NMR, and elemental analysis). These compounds were biologically evaluated for their α-amylase and α-glucosidase inhibitory activity, identifying 5f as the most active (IC50 26.67 ± 1.25 μM and 39.12 ± 1.83 μM against α-amylase α-glucosidase, respectively), better than the standard, acarbose. Enzymatic kinetic results showed that 5f and acarbose complete competitive type inhibitors. The structure-activity relationship (SAR) demonstrated that undergoing substitutions on R1 and R2 groups attached to the thiourea/urea moiety chains controlled the activity. Besides, in-silico ADMET study showed that almost title compounds exhibited satisfactory pharmacokinetic properties. In molecular docking study, the top performing compound (5f) exhibited higher binding energies (−5.501 and −6.414 kcal/mol, respectively) showing crucial interactions and that snuggly fit in their active site. To shed light on their mechanism of action, molecular dynamic (MD) simulations approach executed at 100 ns duration authenticated the high stability of 5f-1B2Y and 5f-3A4A complexes. The results of this investigation disclosed that compound 5f may serve as a potential lead, accomplished with in vivo studies, for the management of diabetes.http://www.sciencedirect.com/science/article/pii/S2405844024144076Diabetes mellitusImidazo-isoxazole derivativesα-amylase and α-glucosidase inhibitionEnzymatic kineticsSAR analysisADMET |
| spellingShingle | Etab AlRashidi Siwar Ghannay Abuzar E.A.E. Albadri Majdi Abid Adel Kadri Kaiss Aouadi Design, synthesis, biological evaluation, kinetic studies and molecular modeling of imidazo-isoxazole derivatives targeting both α-amylase and α-glucosidase inhibitors Heliyon Diabetes mellitus Imidazo-isoxazole derivatives α-amylase and α-glucosidase inhibition Enzymatic kinetics SAR analysis ADMET |
| title | Design, synthesis, biological evaluation, kinetic studies and molecular modeling of imidazo-isoxazole derivatives targeting both α-amylase and α-glucosidase inhibitors |
| title_full | Design, synthesis, biological evaluation, kinetic studies and molecular modeling of imidazo-isoxazole derivatives targeting both α-amylase and α-glucosidase inhibitors |
| title_fullStr | Design, synthesis, biological evaluation, kinetic studies and molecular modeling of imidazo-isoxazole derivatives targeting both α-amylase and α-glucosidase inhibitors |
| title_full_unstemmed | Design, synthesis, biological evaluation, kinetic studies and molecular modeling of imidazo-isoxazole derivatives targeting both α-amylase and α-glucosidase inhibitors |
| title_short | Design, synthesis, biological evaluation, kinetic studies and molecular modeling of imidazo-isoxazole derivatives targeting both α-amylase and α-glucosidase inhibitors |
| title_sort | design synthesis biological evaluation kinetic studies and molecular modeling of imidazo isoxazole derivatives targeting both α amylase and α glucosidase inhibitors |
| topic | Diabetes mellitus Imidazo-isoxazole derivatives α-amylase and α-glucosidase inhibition Enzymatic kinetics SAR analysis ADMET |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024144076 |
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