Background:
A number of non-steroidal anti-inflammatory drugs (NSAIDs) including
aspirin, indomethacin, ibuprofen, flufenamic acid, and phenylbutazone are being clinically used to
treat inflammatory disorders. These NSAIDs are associated with serious side effects such as gastric
ulceration, nephrotoxicity, and bleeding. Therefore, the identification of potent and safe therapy
for inflammatory disorders is still of great interest to the medicinal chemist.
Methods:
A series of varyingly substituted benzoyl, acetyl, alkyl ester, and sulfonate ester substituted
coumarins 1-64 were screened for the inhibition of ROS, generated from zymosan activated
whole blood phagocytes, using luminol-enhanced chemiluminescence technique.
Results:
Among all tested compounds, 8 (IC50 = 65.0 ± 3.1 μM), 24 (IC50 = 41.8 ± 1.5 μM), 26
(IC50 = 10.6 ± 2.8 μM), 28 (IC50 = 20.9 ± 1.5 μM), and 41 (IC50 = 4.6 ± 0.3 μM) showed good anti-
inflammatory potential as compared to standard antiinflammatory drug ibuprofen (IC50 = 54.3 ±
1.9 μM). Specifically, compounds 24, 26, 28, and 41 showed superior activity than standard antiinflammatory
drug. Furthermore, compounds 12 (IC50 = 219.0 ± 1.4 μM), 14 (IC50 = 216.5 ± 6.2
μM), 16 (IC50 = 187.4 ± 2.2 μM), and 20 (IC50 = 196.2 ± 2.0 μM) showed moderate ROS inhibitory
activity. Limited SAR study revealed that the hydroxy-substituted compound showed better
ROS inhibition potential in case of 3-benzoyl and 3-ethylester coumarin derivatives. Whereas,
chloro substitution was found to be important in case of 3-acetyl coumarin derivatives. Similarly,
in case of sulfonate ester, chloro, and nitro groups especially at positions -4 and -3 of ring “R”
played vital role in ROS inhibition. Furthermore, cytotoxicity of all active compounds was also
checked on NIH-3T3 cell line. Compounds 12, 14, and 20 were found to be non-cytotoxic. Whereas,
8, 16, 24, 26, 28, and 41 were found to be very weak cytotoxic as compared to standard cycloheximide
(IC50 = 0.13 ± 0.02 μM).
Conclusion:
Identified ROS inhibitors offer the possibility of additional modifications that could
give rise to lead structures for further research in order to obtain more potent, and safer antiinflammatory
agent.
Use of Cyclic Ion Mobility Spectrometry (cIM)-Mass Spectrometry to Study the Intramolecular Transacylation of Diclofenac Acyl Glucuronide
