Synthesis of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives and its potential applications in atherosclerosis.

In the search for novel anti-atherosclerotic agents, we herein report the design, synthesis, and evaluation of a series of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives (5a-5n). Cytotoxicity assessment in RAW 264.7 cells indicated minimal toxicity for most compounds under experimental conditions. Notably, compound 5j exhibited superior anti-inflammatory activity, significantly attenuating intracellular reactive oxygen species (ROS) while maintaining exceptional cytocompatibility (>100% cell viability at 1.25-20 μM) and demonstrating the most potent suppression of lipid accumulation. Mechanistic studies revealed that compound 5j synergistically modulates two key pathways: downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and restoration of cholesterol homeostasis via upregulation of ABCG1, leading to enhanced cholesterol efflux and 69.9% inhibition of foam cell formation at 3.25 μM (p < 0.001). SwissADME predictions indicated that compound 5j possesses favorable membrane permeability, high gastrointestinal absorption, and potential oral bioavailability. These findings establish compound 5j as a potential lead for developing atherosclerosis therapies through coordinated modulation of inflammation and lipid metabolism.