期刊
MEDICINAL CHEMISTRY
卷 14, 期 8, 页码 818-830出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1573406414666180525105325
关键词
beta-Glucuronidase inhibitor; glucuronidation; copper nitrate trihydrate as catalyst; one-pot multicomponent reaction; xenobiotics; 2-oxo-1,2,3,4-tetrahydropyrimidines
资金
- Higher Education Commission (HEC), Pakistan [20-1910]
Background: Glucuronidation is essential for the metabolism and excretion of toxic substances.beta-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 beta-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 beta-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 beta-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 beta-glucuronidase inhibitor (IC50 = 45.75 +/- 2.16 mu M). Compound 20 (IC50 = 1.36 +/- 0.03 mu M) 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 beta-glucuronidase inhibitors with the potential to be investigated further.
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