Synthesis and biological evaluation of novel indole-2-one and 7-aza-2-oxindole derivatives as anti-inflammatory agents.
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.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Gaozhi
G
Chen
Department of Pediatrics, The 2nd Affiliated Hospital, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Lili
L
Jiang
Department of Pediatrics, The 2nd Affiliated Hospital, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Lili
L
Dong
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Zhe
Z
Wang
Department of Pediatrics, The 2nd Affiliated Hospital, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Fengli
F
Xu
Department of Pharmacy, The 5th Affiliated Hospital, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Ting
T
Ding
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Lili
L
Fu
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Qilu
Q
Fang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China ; Wenzhou Undersun Biotchnology Co, Ltd, Wenzhou, Zhejiang, People's Republic of China.
Zhiguo
Z
Liu
Department of Pediatrics, The 2nd Affiliated Hospital, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Xiaoou
X
Shan
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Lishui, Zhejiang, People's Republic of China.
Guang
G
Liang
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D000078183:Oxindoles; D021281:Quantitative Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000078183:Oxindoles; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C022960:2-oxindole
anti-inflammation; macrophages; sepsis