Anti-inflammatory activity of fluorine-substituted benzo[h]quinazoline-2-amine derivatives as NF-κB inhibitors.

Excessive inflammation can cause loss of tissue or organ function, leading to a number of chronic diseases and sometimes even death. Traditional treatment strategies for inflammation have mainly involved steroidal and non-steroidal anti-inflammatory drugs, but both have increasingly prominent side effects. Nuclear factor kappa B (NF-κB) inhibitors with anti-inflammatory properties and low toxicity are a new therapeutic strategy for the treatment of inflammatory diseases. To obtain novel NF-κB inhibitors, a series of 3,4-dihydronaphthalen-1(2H)-one derivatives (DHNs 6a-s), 1,4,5,6-tetrahydrobenzo[h]quinazolin-2-amine derivatives (BQAs 7a-c) and 5,6-dihydrobenzo[h]quinazolin-2-amine derivatives (BQAs 8a-p) were designed and synthesized, and characterized by NMR and HRMS. By evaluating toxicity and anti-inflammatory properties, fluorine-substituted 8c showed more potential anti-inflammatory activity and lower toxicity. 8c significantly reduced the phosphorylation of IκBα and p65, thereby inhibiting the NF-κB signaling pathway. In addition, 8c markedly decreased reactive oxygen species (ROS) production and downregulated the expression of NOD-like receptor pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC) and cysteine aspartate protein hydrolase-1 (caspase-1). Therefore, compound 8c is expected to be a candidate compound for NF-κB inhibition and deserves further research and development.

Synthesis, biological evaluation and molecular docking studies of novel diosgenin derivatives as anti-inflammatory agents.

Thirty-two novel DG F-spiroacetal ring-opening derivatives, including 24 acetylated derivatives and 8 nitrogenous derivatives, were designed and synthesized from diosgenin (DG). The cytotoxicity of the novel derivatives was evaluated by MTT assay, except for compounds 4a, 4e, 4i, 4 l, 5a and 5 h, which were potentially cytotoxic to RAW264.7 cells, all the other derivatives had no significant cytotoxicity. The NO release inhibitory activities of novel derivatives were screened by Griess method. The results showed that the anti-inflammatory activity of the DG acetylated derivatives was stronger than the nitrogenous derivatives, and 4a-4 m containing acetyl groups at the 3-position may have better anti-inflammatory effects than 5a-5 k containing free hydroxyl groups. In ELISA assay, compound 4 m exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by LPS with IC50 values 0.449 ± 0.050 µM. The results of docking experiments showed that 4 m has a good affinity for p65 protein.

Anti-neuroinflammatory effects of novel 5,6-dihydrobenzo[h]quinazolin-2-amine derivatives in lipopolysaccharide-stimulated BV2 microglial cells.

Neuroinflammation is an intricate process that is associated with both normal and pathological conditions. Microglia-mediated neuroinflammation is known to lead to various neurodegenerative and neurological disorders. A series of 3,4-dihydronaphthalen-1(2H)-one derivatives (1-15) and novel 5,6-dihydrobenzo[h]quinazolin-2-amine derivatives (16-30) were synthesized and characterized by various analytical methods, such as NMR and HRMS. All compounds were evaluated for toxicity, screened for their anti-neuroinflammatory properties, and investigated for the potential molecular mechanism of lipopolysaccharide (LPS) induction in BV2 microglia. Structure activity relationship analysis showed that compound 17 substituted by the 7-fluorine atom on the A-ring and the 3-methoxy on the D-ring had more potential anti-neuroinflammatory activity by inhibiting the secretion of cytokines TNF-α and IL-6. The results of western blotting assay showed that 17 significantly blocked the activation and phosphorylation of IκBα, significantly reduce the expression of NLRP3 inflammatory vesicle-associated proteins, and thus inhibit the activation of NF-κB pathway. Thus, compound 17 was demonstrated to be an excellent potential therapeutic agent for the treatment of neuroinflammation-related diseases.