Oleanolic acid analogs as NO, TNF-α and IL-1β inhibitors: Synthesis, biological evaluation and docking studies

A series of oleanolic acid analogs, characterized by structural modifications at position C-3 and C-28 of oleanane skeleton were synthesized and assessed for antiinflammatory potential towards lipopolysaccharide (LPS) induced nitric oxide (NO) production in macrophages. Results revealed that all the synthesized analogs of oleanolic acid inhibit NO production with an IC50 of 2.66-41.7 mu M as compared to the specific nitric oxide synthase (NOS) inhibitor, L-NAME (IC50 = 69.21 and 73.18 mu M on RAW 264.7 and J774A.1 cells, respectively) without affecting the cell viability when tested at their half maximal concentration. The most potent NO inhibitors (2, 8, 9 and 10) at a concentration of 20 mu g/mL also demonstrated mild inhibition (27.9-51.9%) of LPS-induced tumor necrosis factor alpha (TNF-alpha) and weak inhibition (11.1-37.5%) towards interleukin 1-beta (IL-1 beta) production in both the cells. The present study paves a direction that analogs of oleanolic acid can be employed as a lead in the development of potent NO inhibitors. Molecular docking studies also showed that 10 (with top Goldscore docking pose 19.05) showed similar interaction as that of co-crystallized inhibitor and, thereby, helps to design the potent inhibitors of TNF-alpha. (C) 2014 Elsevier Ltd. All rights reserved.