2. Academic Validation
  3. Synthesis, structure-activity relationships and preliminary mechanism study of N-benzylideneaniline derivatives as potential TLR2 inhibitors

Synthesis, structure-activity relationships and preliminary mechanism study of N-benzylideneaniline derivatives as potential TLR2 inhibitors

  • Bioorg Med Chem. 2018 May 1;26(8):2041-2050. doi: 10.1016/j.bmc.2018.03.001.
Shaoyi Cai 1,  Gengzheng Zhu 1,  Xiaohong Cen 1,  Jingjie Bi 1,  Jingru Zhang 1,  Xiaoshan Tang 1,  Kun Chen 2,  Kui Cheng 3
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 The Joint Research Center of Guangzhou University and Keele Univeristy for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China. Electronic address: Kchennju@hotmail.com.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: chengk@smu.edu.cn.
PMID: 29534935 DOI: 10.1016/j.bmc.2018.03.001
Abstract

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.

Keywords

Inflammatory cytokines; Schiff base derivatives; Small molecule antagonist; Toll-like receptor 2.

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