Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti‐Neuroinflammatory Agents for Ischemic Stroke

Abstract

Benzoxepane derivatives were designed and synthesized, and one hit compound emerged as being effective in vitro with low toxicity. In vivo, this hit compound ameliorated both sickness behavior through anti‐inflammation in LPS‐induced neuroinflammatory mice model and cerebral ischemic injury through anti‐neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing for the hit compound using photoaffinity probes led to identification of PKM2 as the target protein responsible for anti‐inflammatory effect of the hit compound. Furthermore, the hit exhibited an anti‐neuroinflammatory effect in vitro and in vivo by inhibiting PKM2‐mediated glycolysis and NLRP3 activation, indicating PKM2 as a novel target for neuroinflammation and its related brain disorders. This hit compound has a better safety profile compared to shikonin, a reported PKM2 inhibitor, identifying it as a lead compound in targeting PKM2 for the treatment of inflammation‐related diseases.

Trifluoromethyl-substituted 3,5-bis(arylidene)-4-piperidones as potential anti-hepatoma and anti-inflammation agents by inhibiting NF-кB activation

“…Lipopolysaccharide (LPS) is a key constituent of Gram-negative bacterial endotoxin, which is used to induce an inflammatory response in corresponding inflammatory cells 37 . TNF- α and IL-6 are two kinds of representative pro-inflammatory factors, which produced by LPS-stimulated RAW264.7 macrophage 38 . In our pre-experiments, the toxicity against RAW264.7 macrophagocyte for all title compounds was tested by the MTT assay, and the results were listed in Table 2 .…”

Exercise-Linked Irisin Prevents Mortality and Enhances Cognition in a Mice Model of Cerebral Ischemia by Regulating Klotho Expression

“…Some studies demonstrated that it might be due to the increased release of reactive oxygen species (ROS) after the recovery of blood perfusion in the ischemic area, leading to lipid peroxidation and inflammatory reaction in the brain and then damaging the functional regions related to cognition [ 31 , 32 ]. The contents of lipids and polyunsaturated fatty acids are abundant in the brain.…”

Crystal structure of (E)-2-((2-methoxy-3-pyridyl)methylene)-7-fluoro-3,4-dihydronaphthalen-1(2H)-one, C17H14FNO2

“…It has been reported that proinflammatory cytokines [tumor necrosis factor (TNF-α), interleukin (IL)-6, IL-1β] secreted from M1 microglia increase blood-brain barrier (BBB) permeability by activating the nuclear factor kappa B (NF-κB) signaling pathway during inflammatory neurodegenerative diseases in CNS [6][7][8]. Concomitantly, the disruption of the blood-brain barrier can result in severe inflammatory response that aggravates the brain injury [9]. In addition, activated microglia can produce reactive oxygen species (ROS), which may indirectly induce neuroinflammation by activating NF-κB [10,11].…”