title: Selection, synthesis, and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling inhibitors.
abstract: Inhibition of TLR4 signaling is an important therapeutic strategy for intervention in the etiology of several pro-inflammatory diseases. There has been intensive research in recent years aiming to explore this strategy, and identify small molecule inhibitors of the TLR4 pathway. However, the recent failure of a number of advanced drug candidates targeting TLR4 signaling (e.g., TAK242 and Eritoran) prompted us to continue the search for novel chemical scaffolds to inhibit this critical inflammatory response pathway. Here we report the identification of a group of new TLR4 signaling inhibitors through a cell-based screening. A series of arylidene malonate analogs were synthesized and assayed in murine macrophages for their inhibitory activity against LPS-induced nitric oxide (NO) production. The lead compound 1 (NCI126224) was found to suppress LPS-induced production of nuclear factor-kappaB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO) in the nanomolar-low micromolar range. Taken together, this study demonstrates that 1 is a promising potential therapeutic candidate for various inflammatory diseases.
authors.affiliation: Department of Chemistry and Biochemistry and BioFrontiers Institute, 596 University of Colorado at Boulder, Boulder, CO 80309-0596, USA.
authors.forename: Shuting
authors.initials: S
authors.lastname: Zhang
authors.forename: Kui
authors.initials: K
authors.lastname: Cheng
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008314:Malonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001597:Benzylidene Compounds; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008314:Malonates; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C578258:dimethyl 2-(2-nitrobenzylidene)malonate; D009569:Nitric Oxide