Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitors
Abstract α-Glucosidase is an important target in treating type 2 diabetes, and thus, the inhibition of this enzyme could delay sugar digestion and avoid postprandial hyperglycemia. Previous studies revealed that some pyrimidine and piperazine derivatives showed good affinity towards α-glucosidase. I...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-06104-8 |
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| author | Noval Herfindo Pirun Mikled Neni Frimayanti Thanyada Rungrotmongkol Warinthorn Chavasiri |
| author_facet | Noval Herfindo Pirun Mikled Neni Frimayanti Thanyada Rungrotmongkol Warinthorn Chavasiri |
| author_sort | Noval Herfindo |
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| description | Abstract α-Glucosidase is an important target in treating type 2 diabetes, and thus, the inhibition of this enzyme could delay sugar digestion and avoid postprandial hyperglycemia. Previous studies revealed that some pyrimidine and piperazine derivatives showed good affinity towards α-glucosidase. In continuing efforts toward the development of α-glucosidase inhibitor, a series of pyrimidinyl-piperazine carboxamide 6–22 containing chiral center have been synthesized. The inhibition activity was evaluated against α-glucosidase from Saccharomyces cerevisiae. All tested compounds exhibit excellent inhibition effects compared to acarbose (IC50 = 817.38 µM). Compounds bearing S-configurations at the chiral center displayed up to 5-fold more active than R-configurations. Among them, compounds 7c, 17c, 21c, and 22c were the top four compounds with IC50 values in a range of 0.4–1.5 µM. A kinetic study revealed that competitive inhibition as their mechanism of action. The results of the computational study indicated that hydrophobic interactions were the key factor in this activity. Moreover, molecular dynamics simulation showed that the 21c/α-glucosidase complex provided more stability by maintaining a consistent binding pose. MM-GBSA analysis revealed that the binding energy of 21c was approximately 11 kcal/mol lower than its counterpart, confirming the superiority of the S-configuration. The cytotoxicity test indicated that the top four compounds were not toxic to normal cells at the given IC50 value. Hence, these compounds are promising candidate as α-glucosidase inhibitors. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-604fc7c5f6ee40c49868a659ff35ae672025-08-20T03:45:19ZengNature PortfolioScientific Reports2045-23222025-07-0115111610.1038/s41598-025-06104-8Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitorsNoval Herfindo0Pirun Mikled1Neni Frimayanti2Thanyada Rungrotmongkol3Warinthorn Chavasiri4Department of Chemistry, Faculty of Science, Center of Excellence in Natural Products Chemistry, Chulalongkorn UniversityProgram in Biotechnology, Faculty of Science, Chulalongkorn UniversitySekolah Tinggi Ilmu Farmasi (STIFAR)Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn UniversityDepartment of Chemistry, Faculty of Science, Center of Excellence in Natural Products Chemistry, Chulalongkorn UniversityAbstract α-Glucosidase is an important target in treating type 2 diabetes, and thus, the inhibition of this enzyme could delay sugar digestion and avoid postprandial hyperglycemia. Previous studies revealed that some pyrimidine and piperazine derivatives showed good affinity towards α-glucosidase. In continuing efforts toward the development of α-glucosidase inhibitor, a series of pyrimidinyl-piperazine carboxamide 6–22 containing chiral center have been synthesized. The inhibition activity was evaluated against α-glucosidase from Saccharomyces cerevisiae. All tested compounds exhibit excellent inhibition effects compared to acarbose (IC50 = 817.38 µM). Compounds bearing S-configurations at the chiral center displayed up to 5-fold more active than R-configurations. Among them, compounds 7c, 17c, 21c, and 22c were the top four compounds with IC50 values in a range of 0.4–1.5 µM. A kinetic study revealed that competitive inhibition as their mechanism of action. The results of the computational study indicated that hydrophobic interactions were the key factor in this activity. Moreover, molecular dynamics simulation showed that the 21c/α-glucosidase complex provided more stability by maintaining a consistent binding pose. MM-GBSA analysis revealed that the binding energy of 21c was approximately 11 kcal/mol lower than its counterpart, confirming the superiority of the S-configuration. The cytotoxicity test indicated that the top four compounds were not toxic to normal cells at the given IC50 value. Hence, these compounds are promising candidate as α-glucosidase inhibitors.https://doi.org/10.1038/s41598-025-06104-8 |
| spellingShingle | Noval Herfindo Pirun Mikled Neni Frimayanti Thanyada Rungrotmongkol Warinthorn Chavasiri Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitors Scientific Reports |
| title | Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitors |
| title_full | Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitors |
| title_fullStr | Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitors |
| title_full_unstemmed | Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitors |
| title_short | Chiral pyrimidinyl-piperazine carboxamide derivatives as potent yeast α-glucosidase inhibitors |
| title_sort | chiral pyrimidinyl piperazine carboxamide derivatives as potent yeast α glucosidase inhibitors |
| url | https://doi.org/10.1038/s41598-025-06104-8 |
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