New 1,3,4-oxadiazole/oxime hybrids: Design, synthesis and anti-inflammatory activity

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for their anti-inflammatory, antipyretic, and analgesic effects. However, their clinical use is often limited by gastrointestinal (GI) toxicity, largely due to the presence of a free carboxylic acid group in their structure. To address this limitation, bioisosteric replacement with heterocycles like 1,3,4-oxadiazole, and incorporation of nitric oxide (NO)-releasing functionalities such as oximes, have emerged as promising strategies. In this study, a series of eight novel 1,3,4-oxadiazole/oxime hybrid derivatives (5a–5h) were synthesized to combine these dual benefits: improved GI safety and enhanced anti-inflammatory efficacy. All compounds were structurally elucidated by FT-IR, ¹H NMR, ¹³C NMR, and HPLC (purification ≥96%). Their bioactivity was assayed by in vitro egg albumin denaturation, in vivo carrageenan-induced paw edema, and DPPH radical scavenging. Ulcerogenic activity and NO-releasing activity were also evaluated. Compound 5a was the most lead-like compound with 68.6% inhibition of paw edema, close to that of control drug indomethacin (71.2%). It also exhibited moderate antioxidant activity (56.8 mg TE/g in DPPH assay) and caused significant decrease in ulcer index compared to indomethacin, reflecting lesser GI toxicity. In silico pharmacokinetic prediction using SwissADME confirmed good drug-likeness of promising compounds. Molecular docking studies with inducible nitric oxide synthase (iNOS, PDB ID: 3e7g) afterwards demonstrated that compound 5a, particularly its Z-isomer is well suited to form vital interactions such as π-π stacking with protoporphyrin IX as well as ionic salt bridges with Asp382 or Arg388 via the oxime group. Docking scores were comparable to the co-crystallized ligand AR-C95791 (ds: –5.60 kcal/mol, RMSD: 0.550), and this reinforces the prospects of both enzyme inhibition and NO-mediated cytoprotection. These findings confirm compound 5a as a potential dual-action anti-inflammatory agent with enhanced potency and safety.