Structure-based design, synthesis and biological evaluation of β-glucuronidase inhibitors.
Using structure-based virtual screening approach, a coumarin derivative (1) was identified as β-glucuronidase inhibitor. A focused library of coumarin derivatives was synthesized by eco-benign version of chemical reaction, and all synthetic compounds were characterized by using spectroscopy. These compounds were found to be inhibitor of β-glucuronidase with IC50 values in a micromolar range. All synthetic compounds exhibited interesting inhibitory activity against β-glucuronidase, however, their potency varied substantially from IC50 = 9.9-352.6 µM. Of twenty-one compounds, four exhibited a better inhibitory profile than the initial hit 1. Interestingly, compounds 1e, 1k, 1n and 1p exhibited more potency than the standard inhibitor with IC50 values 34.2, 21.4, 11.7, and 9.9 µM, respectively. We further studied their dose responses and also checked our results by using detergent Triton ×-100. We found that our results are true and not affected by detergent.
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan, khalid.khan@iccs.edu.
Khalid M
KM
Khan
Nida
N
Ambreen
Muhammad
M
Taha
Sobia A
SA
Halim
Zaheer-ul-Haq
Shagufta
S
Naureen
Saima
S
Rasheed
Shahnaz
S
Perveen
Sajjad
S
Ali
Mohammad Iqbal
MI
Choudhary
D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure
D004791:Enzyme Inhibitors; D005966:Glucuronidase