2. Academic Validation
  3. Design, synthesis and anti-rheumatoid arthritis activity of target TLR4 inhibitors

Design, synthesis and anti-rheumatoid arthritis activity of target TLR4 inhibitors

  • Bioorg Med Chem. 2024 Jan 1:97:117539. doi: 10.1016/j.bmc.2023.117539.
Wenbin Wang 1,  Shiyang Zhou 2,  Wenming Jiang 1,  Guangying Chen 3
Affiliations

Affiliations

  • 1 Chongqing Chemical Industry Vocational College, Chongqing 401228, China; Chongqing (Changshou) Green Chemical and Material Industry Technology Research Institute, Chongqing 401228, China.
  • 2 Chongqing Chemical Industry Vocational College, Chongqing 401228, China; Chongqing (Changshou) Green Chemical and Material Industry Technology Research Institute, Chongqing 401228, China; Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, Hainan Normal University, Haikou 571158, China; Chongqing Academy of Traditional Chinese Medicine, Chongqing 400065, China; Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China. Electronic address: [email protected].
  • 3 Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, Hainan Normal University, Haikou 571158, China. Electronic address: [email protected].
PMID: 38070351 DOI: 10.1016/j.bmc.2023.117539
Abstract

A series of 1-(2-oxocyclohexyl)butane-1, 3-dione derivatives were designed and synthesized as TLR4 inhibitors by modifying the core structure of the lead compound ((6, 8-dioxo-1, 2, 3, 4, 6, 7, 8, 8a-octahydronaphthalen-2-yl) carbamate)). In vitro, compound 3p significantly inhibited the proliferation of rat synovial cells, inhibited the proliferation of LPS-induced RAW264.7 cells, and inhibited TLR4 activity, with IC50 values of 1.21 ± 0.09 μM, 0.73 ± 0.05 μM and 0.43 ± 0.03 μM, respectively, which was superior to the positive control methotrexate. In vivo anti-rheumatoid arthritis evaluation, compound 3p can significantly inhibit the inflammatory factors TNF-α, IL-1β and IL-6, so as to achieve the therapeutic purpose. In the preliminary mechanism study, compound 3p has obvious regulatory effects on the abnormal increase of TLR4, JAK2 and STAT3 protein and gene expression related to inflammatory signaling pathway in RAW264.7 cells. In summary, this study aims to develop more effective candidates for rheumatoid arthritis.

Keywords

RAW264.7 cells; Rheumatoid arthritis; TLR4 inhibitors.

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