Synthesis of 2-Aminopyrimidine Derivatives and Their Evaluation as β -Glucuronidase Inhibitors: In Vitro and In Silico Studies

Currently the discovery and development of potent -glucuronidase inhibitors is an active area of research due to the observation that increased activity of this enzyme is associated with many pathological conditions, such as colon cancer, renal diseases, and infections of the urinary tract. In this...

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Published in:Molecules (Basel, Switzerland) Switzerland), 2022-11, Vol.27 (22), p.7786
Main Authors: Iqbal, Sarosh, Shaikh, Nimra Naveed, Khan, Khalid Mohammed, Kiran, Shumaila, Naz, Sehrish, Ul-Haq, Zaheer, Perveen, Shahnaz, Choudhary, M Iqbal
Format: Article
Language:English
Subjects:
2-Amino-4,6-dichloropyrimidine
Amines
Antioxidants
Cancer
catalyst-free synthesis
Catalysts
Colon cancer
Crystal structure
Enzyme Inhibitors - chemistry
Enzymes
Glucaric acid
Glucuronidase - metabolism
Hydrogen bonds
Inhibitors
Magnetic resonance spectroscopy
Molecular Docking Simulation
NMR
NMR spectroscopy
Nuclear magnetic resonance
nucleophilic substitution reaction
Proteins
Software
solvent-free synthesis
Structure-Activity Relationship
Triethylamine
Urinary tract
β-glucuronidase inhibitors
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Summary:Currently the discovery and development of potent -glucuronidase inhibitors is an active area of research due to the observation that increased activity of this enzyme is associated with many pathological conditions, such as colon cancer, renal diseases, and infections of the urinary tract. In this study, twenty-seven 2-aminopyrimidine derivatives were synthesized by fusion of 2-amino-4,6-dichloropyrimidine with a variety of amines in the presence of triethylamine without using any solvent and catalyst, in good to excellent yields. All synthesized compounds were characterized by EI-MS, HREI-MS and NMR spectroscopy. Compounds were then evaluated for their -glucuronidase inhibitory activity, and among them, compound (IC = 2.8 ± 0.10 µM) showed an activity much superior to standard D-saccharic acid 1,4-lactone (IC = 45.75 ± 2.16 µM). To predict the binding mode of the substrate and -glucuronidase, in silico study was performed. Conclusively, this study has identified a potent -glucuronidase inhibitor that deserves to be further studied for the development of pharmaceutical products.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27227786