Design, Synthesis, Molecular Modelling, and Biological Evaluation of Oleanolic Acid-Arylidene Derivatives as Potential Anti-Inflammatory Agents

Introduction: Oleanolic acid, a pentacyclic triterpenic acid, is widely distributed in medicinal plants and is the most commonly studied triterpene for various biological activities, including anti-allergic, anti-cancer, and anti-inflammatory. Methods: The present study was carried out to synthesize arylidene derivatives of oleanolic acid at the C-2 position by Claisen Schmidt condensation to develop more effective anti-inflammatory agents. The derivatives were screened for anti-inflammatory activity by scrutinizing NO production inhibition in RAW 264.7 cells induced by LPS and their cytotoxicity. The potential candidates were further screened for inhibition of LPS-induced interleukin (IL-6) and tumour necrosis factor-alpha (TNF-alpha) production in RAW 264.7 cells. Results: The results of in vitro studies revealed that derivatives 3d, 3e, 3L, and 3o are comparable to that of the oleanolic acid on the inhibition of TNF-alpha and IL-6 release. However, derivative 3L was identified as the most potent inhibitor of IL-6 (77.2%) and TNF-alpha (75.4%) when compared to parent compound, and compounds 3a (77.18%), 3d (71.5%), and 3e (68.8%) showed potent inhibition of NO than oleanolic acid (65.22%) at 10 mu M. Besides, from docking score and Cyscore analysis analogs (3e, 3L, 3n) showed greater affinity towards TNF-alpha and IL-1 beta than dexamethasone. Conclusion: Herein, we report a series of 15 new arylidene derivatives of oleanolic acid by Claisen Schmidt condensation reaction. All the compounds synthesized were screened for their anti-inflammatory activity against NO, TNF-alpha and IL-6. From the data, it was evident that most of the compounds exhibited better anti-inflammatory activity.

Automated summary

In this study, a series of 15 new arylidene derivatives of oleanolic acid were synthesized by Claisen Schmidt condensation reaction. Among them, derivative 3L was identified as the most potent inhibitor of IL-6 and TNF-alpha, while compounds 3a, 3d, and 3e showed potent inhibition of NO. In addition, analogs 3e, 3L, and 3n exhibited greater affinity towards TNF-alpha and IL-1 beta than dexamethasone. These findings suggest that the synthesized compounds have promising anti-inflammatory potential.