Synthesis, structure-activity relationships and preliminary mechanism study of N-benzylideneaniline derivatives as potential TLR2 inhibitors.
Toll-like receptor 2 (TLR2) can recognize pathogen-associated molecular patterns to defense against invading organisms and has been represents an attractive therapeutic target. Until today, none TLR2 small molecule antagonist have been developed in clinical trial. Herein, we designed and synthesized 50 N-benzylideneaniline compounds with the help of CADD. And subsequent in vitro studies leading to the optimized compound SMU-A0B13 with most potent inhibitory activity to TLR2 (IC50=18.21 ± 0.87 μM). Preliminary mechanism studies indicated that this TLR2 inhibitor can work through the NF-κB signaling pathway with high specificity and low toxicity, and can also efficiently downregulate inflammatory cytokines, such as SEAP, TNF-α and NO in HEK-Blue hTLR2, human PBMC and Raw 264.7 cell lines. Additionally, the docking situation also indicate SMU-A0B13 can well bind to the TLR2-TIR (PDB: 1FYW) active domain, which probably explains the bioactivity.
['Cai|Shaoyi|S|', 'Zhu|Gengzheng|G|', 'Cen|Xiaohong|X|', 'Bi|Jingjie|J|', 'Zhang|Jingru|J|', 'Tang|Xiaoshan|X|', 'Chen|Kun|K|', 'Cheng|Kui|K|']
D000814:Aniline Compounds D000818:Animals D001665:Binding Sites D020134:Catalytic Domain D002478:Cells, Cultured D016207:Cytokines D006801:Humans D007963:Leukocytes, Mononuclear D051379:Mice D062105:Molecular Docking Simulation D016328:NF-kappa B D000067996:RAW 264.7 Cells D015398:Signal Transduction D013329:Structure-Activity Relationship D051195:Toll-Like Receptor 2
Toll-like receptor 2 Small molecule antagonist Inflammatory cytokines Schiff base derivatives