Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitors
Abstract This paper describes the design, development, synthesis, in silico, and in vitro evaluation of fourteen novel heterocycle hybrids as inhibitors of the α-glucosidase enzyme. The primary aim of this study was to explore the potential of novel pyrazole-phthalazine hybrids as selective inhibito...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-87258-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571866753007616 |
|---|---|
| author | Mehrdad Roshan Roghieh Mirzazadeh Azadeh Tajmir-Riahi Mohammad Sadegh Asgari |
| author_facet | Mehrdad Roshan Roghieh Mirzazadeh Azadeh Tajmir-Riahi Mohammad Sadegh Asgari |
| author_sort | Mehrdad Roshan |
| collection | DOAJ |
| description | Abstract This paper describes the design, development, synthesis, in silico, and in vitro evaluation of fourteen novel heterocycle hybrids as inhibitors of the α-glucosidase enzyme. The primary aim of this study was to explore the potential of novel pyrazole-phthalazine hybrids as selective inhibitors of α-glucosidase, an enzyme involved in carbohydrate metabolism, which plays a key role in the management of type 2 diabetes. The rationale for this study stems from the need for new, more effective inhibitors of α-glucosidase with improved efficacy and safety profiles compared to currently available therapies like Acarbose. The synthesized compounds were tested against the yeast α-glucosidase enzyme and showed significantly higher activity than the standard drug Acarbose. The IC50 values ranged from 13.66 ± 0.009 to 494 ± 0.006 μM, compared to the standard drug Acarbose (IC50 = 720.18 ± 0.008). The most effective α-glucosidase inhibitor, 2-acetyl-1-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-3-methyl-1H-pyrazolo[1,2-b]phthalazine-5,10-dione (8l), was identified through a kinetic binding study that yielded an inhibition constant, Ki, of 34.75 µM. All of the pharmacophoric features used in the hybrid design were found to be involved in the interaction with the enzyme’s active site, as expected. Moreover, molecular dynamic simulation and the absorption, distribution, metabolism, and excretion (ADME) have been performed. |
| format | Article |
| id | doaj-art-7d6e407c936043c884972cd5d1b8c332 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-7d6e407c936043c884972cd5d1b8c3322025-02-02T12:16:10ZengNature PortfolioScientific Reports2045-23222025-01-0115111510.1038/s41598-025-87258-3Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitorsMehrdad Roshan0Roghieh Mirzazadeh1Azadeh Tajmir-Riahi2Mohammad Sadegh Asgari3Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology (IUST)Biochemistry Department, Pasteur Institute of IranSchool of Chemistry, College of Science, University of TehranDepartment of Chemistry, Iran University of Science and Technology (IUST)Abstract This paper describes the design, development, synthesis, in silico, and in vitro evaluation of fourteen novel heterocycle hybrids as inhibitors of the α-glucosidase enzyme. The primary aim of this study was to explore the potential of novel pyrazole-phthalazine hybrids as selective inhibitors of α-glucosidase, an enzyme involved in carbohydrate metabolism, which plays a key role in the management of type 2 diabetes. The rationale for this study stems from the need for new, more effective inhibitors of α-glucosidase with improved efficacy and safety profiles compared to currently available therapies like Acarbose. The synthesized compounds were tested against the yeast α-glucosidase enzyme and showed significantly higher activity than the standard drug Acarbose. The IC50 values ranged from 13.66 ± 0.009 to 494 ± 0.006 μM, compared to the standard drug Acarbose (IC50 = 720.18 ± 0.008). The most effective α-glucosidase inhibitor, 2-acetyl-1-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-3-methyl-1H-pyrazolo[1,2-b]phthalazine-5,10-dione (8l), was identified through a kinetic binding study that yielded an inhibition constant, Ki, of 34.75 µM. All of the pharmacophoric features used in the hybrid design were found to be involved in the interaction with the enzyme’s active site, as expected. Moreover, molecular dynamic simulation and the absorption, distribution, metabolism, and excretion (ADME) have been performed.https://doi.org/10.1038/s41598-025-87258-3 |
| spellingShingle | Mehrdad Roshan Roghieh Mirzazadeh Azadeh Tajmir-Riahi Mohammad Sadegh Asgari Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitors Scientific Reports |
| title | Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitors |
| title_full | Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitors |
| title_fullStr | Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitors |
| title_full_unstemmed | Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitors |
| title_short | Rational design, synthesis, in vitro, and in-silico studies of pyrazole‑phthalazine hybrids as new α‑glucosidase inhibitors |
| title_sort | rational design synthesis in vitro and in silico studies of pyrazole phthalazine hybrids as new α glucosidase inhibitors |
| url | https://doi.org/10.1038/s41598-025-87258-3 |
| work_keys_str_mv | AT mehrdadroshan rationaldesignsynthesisinvitroandinsilicostudiesofpyrazolephthalazinehybridsasnewaglucosidaseinhibitors AT roghiehmirzazadeh rationaldesignsynthesisinvitroandinsilicostudiesofpyrazolephthalazinehybridsasnewaglucosidaseinhibitors AT azadehtajmirriahi rationaldesignsynthesisinvitroandinsilicostudiesofpyrazolephthalazinehybridsasnewaglucosidaseinhibitors AT mohammadsadeghasgari rationaldesignsynthesisinvitroandinsilicostudiesofpyrazolephthalazinehybridsasnewaglucosidaseinhibitors |