2-Oxo-1,2,3,4-tetrahydropyrimidines Ethyl Esters as Potent β- Glucuronidase Inhibitors: One-pot Synthesis, In vitro and In silico Studies
Autor: | Khalid Mohammed Khan, Nimra Naveed Shaikh, Sarosh Iqbal, Zaheer Ul-Haq, Shahnaz Perveen, Muhammad Iqbal Choudhary, Sehrish Naz |
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Rok vydání: | 2018 |
Předmět: |
chemistry.chemical_classification
Glucuronidation Pyrimidinones 04 agricultural and veterinary sciences Metabolism 040401 food science In vitro Glucuronidase Molecular Docking Simulation Small Molecule Libraries Structure-Activity Relationship chemistry.chemical_compound 0404 agricultural biotechnology Enzyme Biochemistry chemistry Docking (molecular) Ethyl acetoacetate Drug Discovery Enzyme Inhibitors IC50 |
Zdroj: | Medicinal Chemistry. 14:818-830 |
ISSN: | 1573-4064 |
Popis: | BACKGROUND Glucuronidation is essential for the metabolism and excretion of toxic substances. β-Glucuronidase enzyme slows down the process of glucuronidation, and thus plays an important role in the on-set of colorectal carcinoma, and many other diseases. Inhibition of β- glucuronidase activity is thus identified as an important approach for the treatment of several diseases. OBJECTIVE Current study was aimed to synthesize a library of 2-oxo-1,2,3,4-tetrahydropyrimidine and to evaluate their β-glucuronidase inhibitory activity, and their mode of enzyme inhibition. METHOD We synthesized a series of 2-oxo-1,2,3,4-tetrahydropyrimidines 1-25 by fusing urea, ethyl acetoacetate, and a variety of aldehydes using copper nitrate trihydrate as catalyst. All synthesized compounds were evaluated for their in vitro β-glucuronidase inhibitory activity. In addition, molecular docking studies were also performed by using MOE docking tools. RESULTS Eighteen compounds showed inhibitory activity better than the standard D-saccharic acid 1,4-lactone, a well known β-glucuronidase inhibitor (IC50 = 45.75 ± 2.16 µM). Compound 20 (IC50 = 1.36 ± 0.03 µM) showed an excellent inhibitory activity, thirty-five folds superior to the standard. Docking results highlighted the role of various chemical moieties at different positions on 2- oxo-1,2,3,4-tetrahydropyrimidine skeleton in enzyme inhibitory activity. CONCLUSION This study has identified a class of potent β-glucuronidase inhibitors with the potential to be investigated further. |
Databáze: | OpenAIRE |
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