Background: Pro-inflammatory cytokines trigger immune cells to produce and release interleukin, interferon, and Tumor necrosis factors. In pathological conditions, the excessive release of these cytokines can cause various autoimmune diseases such as (rheumatoid arthritis, psoriasis, and irritable bowel syndrome).   Methods: This study was conducted to synthesizefour derivatives of 1,2,4-triazole linked to Schiff bases.The synthesis was started by converting of ibuprofen to ibuprofen ethyl ester. Then converted to ibuprofen hydrazide by reaction with hydrazine hydrate. After that ibuprofen hydrazide is converted to an intermediate salt of potassium carbazinate by the reaction with an alcoholic solution of KOH and CS₂ in a cold condition which undergoes the cyclization reaction with hydrazine hydrate in an aqueous condition to form 1,2,4 triazole. The derivatives of triazole were converted to Schiff base by reaction with different aromatic aldehydes.   Results: The structure of prepared compounds was confirmed by using FTIR, ¹HNMR, ¹³CNMR, and MS. The inhibitory effect of newly synthesized compounds against TNF-α was evaluated in comparison with standard ibuprofen. It showed good to moderate activity upon inhibition of TNF-α   Conclusion: The synthesized compounds are prepared successfully according to 1H-NMR, 13C-NMR, FT-IR, and mass spectroscopy data, and they showed a good to moderate inhibition rate of TNF-α compared to reference drug (Ibuprofen) they may use in the treatment of various autoimmune disease.