Design, synthesis and biological evaluation of novel 2-sulfonylindoles as potential anti-inflammatory therapeutic agents for treatment of acute lung injury

• Published in: European journal of medicinal chemistry Vol. 160; pp. 120 - 132
• Main Authors: Xia, Qinqin, Bao, Xiaodong, Sun, Chuchu, Wu, Di, Rong, Xiaona, Liu, Zhiguo, Gu, Yugui, Zhou, Jianmin, Liang, Guang
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-12-2018
• Subjects: 2-Sulfonylindoles; Acute lung injury; Acute Lung Injury - drug therapy; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Animals; Anti-inflammatory; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cytokines - analysis; Cytokines - biosynthesis; Dose-Response Relationship, Drug; Drug Design; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Macrophage; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Molecular Structure; SAR; Structure-Activity Relationship; Acute lung injury; 2-Sulfonylindoles; SAR; Anti-inflammatory; Macrophage
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.10.014

Acute lung injury (ALI) is primarily driven by inflammation that severely impacts lung function. Novel 2-sulfonylindoles were recently shown to exhibit anti-inflammatory activity through the inhibition of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. Here, we synthesized 31 compounds which contained 2-sulfonylindole structure. The compounds 8a, 9g, 9h and 9k exhibited dose-dependent anti-inflammatory activity in vitro. Structural-activity relationship analysis revealed that the introduction of sulfonyl group in indole nucleus may be successful to obtain new anti-inflammatory structures and leads. The compounds 9h and 9k also decreased liposaccharide (LPS)-induced IL-6, IL-1β and vascular cell adhesion molecule-1 (VCAM-1) mRNA expression, both in vitro and in an in vivo model of ALI. Furthermore, the compounds 9h and 9k at a high dose (20 mg/kg) significantly protected against LPS-induced ALI in mice. These results show that compounds 9h and 9k could be a promising lead structure for the treatment of ALI.
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•31 2-sulfonylindole derivatives were synthesized and evaluated.•Active compounds exhibited anti-inflammatory activities through the inhibition of TNF-α and IL-6.•Compound 9h and 9k attenuated LPS-induced acute lung injury in mice.•Compound 9h and 9k could be lead compounds as ALI therapeutic agents.