2-Oxo-1,2,3,4-tetrahydropyrimidines Ethyl Esters as Potent β- Glucuronidase Inhibitors: One-pot Synthesis, In vitro and In silico Studies
- Med Chem. 2018;14(8):818-830. doi: 10.2174/1573406414666180525105325.
- 1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
- 2. Department of Applied Chemistry, Government College University Faisalabad-38000, Pakistan.
- 3. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia.
- 4. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
- 5. PCSIR Laboratories Complex Karachi, Shahrahe- Dr. Salimuzzaman Siddiqui, Karachi-75280, Pakistan.
- 6. Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah-214412, Saudi Arabia.
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.