Synthesis, Molecular Docking and α-Glucosidase Inhibitory Activity Study of 2,4,6-triaryl pyrimidine Derivatives

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Author(s): Mohammed Hussen Bule, Roghaieh Esfandyari, Tadesse Bekele Tafesse, Mohsen Amini*, Mohammad Ali Faramarzi, Mohammad Abdollahi.

Journal Name: Letters in Drug Design & Discovery

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Background: α-Glucosidase inhibitors hinder the carbohydrate digestion and play an important role in the treatment of diabetes mellitus. The α-glucosidase inhibitors available on market are acarbose, miglitol and voglibose. However, the use of acarbose is diminishing due to related side effects like diarrhea, blotting and abdominal distension.

Objectives: This study aimed to synthesize 2-aryl-4,6-diarylpyrimidine derivatives, screen their α-glucosidase inhibitory activity, perform kinetic and molecular docking studies.

Methods: A series of 2,4,6-triaryl pyrimidine derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Pyrimidine derivatives 4a-m were synthesized via a two-step reaction with a yield between 49 and 93%. The structure of the synthesized compounds was confirmed by different spectroscopic techniques (IR, NMR, MS and Elemental analysis). The in vitro α-glucosidase inhibition activities of the synthesized compounds 4a-m was also evaluated against Saccharomyces cerevisiae α-glucosidase.

Results: Majority of synthesized compounds had α-glucosidase inhibitory activity. Particularly compounds 4b and 4g were the most active compounds with an IC50 value of 125.2± 7.2 and 139.8 ± 8.1 µM respectively. The kinetic study performed for the most active compound 4d revealed that the compound was a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with Ki of 122 µM. The molecular docking study also revealed that the two compounds have important binding interactions with the enzyme active site.

Conclusion: 2,4,6-triarylpyrimidine derivative 4a-m were synthesized and screened for α-glucosidase inhibitory activity. Most of the synthesized compounds possess α-glucosidase inhibitory activity and compound 4b demonstrated the most significant inhibitory action as compared to acarbose.

Keywords: α-Glucosidase inhibitor, Pyrimidine, Synthesis, Enzyme assay, Kinetic study, Docking

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(E-pub Ahead of Print)
DOI: 10.2174/1570180817666200103130536
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