Discovery of anti-inflammatory agents from 3, 4-dihydronaphthalene-1(2H)-one derivatives by inhibiting NLRP3 inflammasome activation

• Published in: European journal of medicinal chemistry Vol. 268; p. 116284
• Main Authors: Li, Wen-Xuan, Yu, Lu, Chi, Jiang-Bo, Wang, Ji-Peng, Liu, Yong-Jun, Wang, Chun-Hua, Zhang, Meng, Hou, Gui-Ge
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-03-2024
• Subjects: 3,4-Dihydronaphthalene-1(2H)-one; Anti-inflammatory; Anti-Inflammatory Agents - pharmacology; Inflammasomes; Molecular Docking Simulation; NF-kappa B - metabolism; NF-κB pathway; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome inhibitor; Anti-inflammatory; 3,4-Dihydronaphthalene-1(2H)-one; NLRP3 inflammasome inhibitor; NF-κB pathway
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116284

NLRP3 inflammatory vesicles are a polymer of cellular innate immunity composed of a pair of proteins. The continuous activation of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammatory vesicles induces the occurrence and enhancement of inflammatory response. In this study, a series of 3, 4-dihydronaphthalene-1(2H)-one derivatives (DHNs, 6a-u, 7a-e, 8a-n) were synthesized and characterized by NMR and HRMS. We evaluated the cytotoxicity and anti-inflammatory activity of all compounds in vitro, and selected 7a substituted by 7-Br in A-ring and 2-pyridylaldehyde in C-ring as effective lead compounds. Specifically, 7a can block the assembly and activation of NLRP3 inflammasome by down-regulating the expression of NLPR3 and apoptosis-associated speck-like protein containing a CARD (ASC), and inhibiting the production of reactive oxygen species (ROS) and other inflammatory mediators. In addition, 7a inhibits the phosphorylation of inhibitor kappa B alpha (IκBα) and NF-κB/p65 and the nuclear translocation of p65, thereby inhibiting nuclear factor kappa-B (NF-κB) signaling. Molecular docking analysis confirmed that 7a could reasonably bind the active sites of NLRP3, ASC and p65 proteins. Therefore, 7a is predicted as a potential NLRP3 inflammatory vesicle inhibitor and deserves further research and development.
Forty nitrogen-containing heterocyclic substituted DHNs were synthesized. Bromine and N-methylpiperazine substituted 7a exhibit lower toxicity and higher anti-inflammatory activity. 7a can block IκBα activation and phosphorylation of p65 and reduce the expression of NLRP3 to inhibit NF-κB and NLRP3 inflammasome activation. [Display omitted]
•Forty nitrogen-containing heterocyclic substituted DHNs were synthesized.•Bromine and N-methylpiperazine substituted 7a exhibited lower toxicity and higher anti-inflammatory activity.•7a inhibited LPS-induced secretion of inflammatory cytokines and nuclear translocation of p65 in RAW246.7 cells.•7a can block IκBα activation and phosphorylation of p65 to inhibit NF-κB and NLRP3 inflammasome activation.