2-Oxo-1,2,3,4-tetrahydropyrimidines Ethyl Esters as Potent β- Glucuronidase Inhibitors: One-pot Synthesis, In vitro and In silico Studies

Author(s): Sarosh Iqbal*, Nimra N. Shaikh, Khalid M. Khan*, Sehrish Naz, Zaheer Ul-Haq, Shahnaz Perveen, Muhammad I. Choudhary*

Journal Name: Medicinal Chemistry

Volume 14 , Issue 8 , 2018

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Graphical Abstract:


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.

Keywords: β-Glucuronidase inhibitor, glucuronidation, copper nitrate trihydrate as catalyst, one-pot multicomponent reaction, 2-oxo-1, 2, 3, 4-tetrahydropyrimidines, xenobiotics.

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Article Details

Year: 2018
Published on: 24 May, 2018
Page: [818 - 830]
Pages: 13
DOI: 10.2174/1573406414666180525105325
Price: $65

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