Synthesis and biological evaluation of novel indole-2-one and 7-aza-2-oxindole derivatives as anti-inflammatory agents

Gaozhi Chen,1,* Lili Jiang,2,* Lili Dong,2 Zhe Wang,1 Fengli Xu,2 Ting Ding,3 Lili Fu,1 Qilu Fang,1 Zhiguo Liu,1,4 Xiaoou Shan,2 Guang Liang1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Pediatrics, The 2nd Affiliated Hospital, 3Department of Pharmacy, The 5th Affiliated Hospital, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China; 4Wenzhou Undersun Biotchnology Co, Ltd, Wenzhou, Zhejiang, People's Republic of China *These authors contribute equally to this work Abstract: Sepsis, a typically acute inflammatory disease, is the biggest cause of death in ICU (intensive care unit). Novel anti-inflammatory alternatives are still in urgent need. In this study, we designed and synthesized 30 indole-2-one and 7-aza-2-oxindole derivatives based on the skeleton of tenidap, and their anti-inflammatory activity was determined by evaluating the inhibitory potency against lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-α and interleukin (IL)-6 release in RAW264.7 macrophages. Quantitative SAR (structure–activity relationship) analysis revealed that a high molecular polarizability and low lipid/water partition coefficient (ALogP) in indole-2-one are beneficial for anti-inflammatory activity. Moreover, compounds 7i and 8e inhibited the expression of TNF-α, IL-6, COX-2, PGES, and iNOS in LPS-stimulated macrophages, and 7i exhibited a significant protection from LPS-induced septic death in mouse models. These data present a series of new indole-2-one compounds with potential therapeutic effects in acute inflammatory diseases. Keywords: anti-inflammation, macrophages, sepsis