Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh’s disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups’, a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC₅₀ = 0.5 µM and 0.3 µM respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions.

肿瘤坏死因子-α是重要的促炎细胞因子，在宿主的免疫系统防御过程中起关键作用，其过表达导致多种炎症性疾病，如类风湿性关节炎，克罗恩病，牛皮癣等。我们对咪唑[1,2- b]的药物化学研究]哒嗪支架：设计，合成和生物学评估。通过在3个位置引入磺酰胺官能团并用（杂）芳基取代6个位置，制备了小的化合物库。筛选所有合成的化合物的脂多糖（LPS）介导的TNF-α抑制活性。生物学数据显示，该系列的大多数化合物均显示出中等至有效的TNF-α抑制活性。化合物5u和5v是该系列中最有效的化合物，其IC ₅₀活性 分别为0.5 µM和0.3 µM。短的SAR表明咪唑[1,2- b]上的3-磺酰基-4-芳基哌啶-4-腈在hPBMC分析中，与3-（4-芳基哌嗪-1-基）磺酰基相比，]哒嗪显示出更好的活性。分子建模研究表明，由于复合物的额外稳定性（由于额外的pi-pi（π-π）堆积，​​氢键相互作用），有效的TNF-α抑制活性为5v。