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

Reyaz Hassan Mir,¹ Goutami Godavari,² Nasir Ali Siddiqui,³ Bilal Ahmad,⁴ Ramzi A Mothana,³ Riaz Ullah,³ Omer M Almarfadi,³ Sanjay M Jachak,² Mubashir Hussain Masoodi<sup>1

1</sup>Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Srinagar, India; ²Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Sahibzada Ajit Singh Nagar, India; ³Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia; ⁴Department of Molecular Science and Technology, Ajou University, Suwon, South Korea

Correspondence: Mubashir Hussain Masoodi
Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India
Tel +919419076525
Email mubashir@kashmiruniversity.ac.in

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-α) 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-α and IL-6 release. However, derivative 3L was identified as the most potent inhibitor of IL-6 (77.2%) and TNF-α (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 10μM. Besides, from docking score and Cyscore analysis analogs (3e, 3L, 3n) showed greater affinity towards TNF-α and IL-1β 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-α and IL-6. From the data, it was evident that most of the compounds exhibited better anti-inflammatory activity.

Keywords: LPS, natural products, IL-1β, IL-6, inflammation, RAW 264.7 cells