Design and Optimization of Acridine-Based p65 G-Quadruplex Stabilizers for the Treatment of Inflammation-Induced Lung Injury and Ulcerative Colitis

Aberrant NF-κB activation drives the pathogenesis of inflammatory diseases. Stabilizing the p65 promoter G-quadruplex (p65 G4) with small molecules to suppress p65 transcription represents a promising anti-inflammatory strategy. Herein, guided by the classical G4 stabilizer BRACO-19 as a hit scaffold, we designed and synthesized 39 new acridine derivatives. Among them, C38 exhibited superior p65 G4 stabilization and anti-inflammatory activity compared to BRACO-19. Mechanistic studies demonstrated that C38 selectively induced and stabilized the p65 G4 structure, thereby inhibiting p65 transcription, reducing p65 protein expression and nuclear translocation, and ultimately suppressing NF-κB signaling. Consequently, C38 significantly attenuated disease progression in mouse models of ALI and UC through potent anti-inflammatory effect. Notably, the safety profile of C38 was dramatically improved compared to BRACO-19. These findings identify C38 as a promising anti-inflammatory candidate and support targeting the p65 G4 with acridine derivatives as a feasible strategy for treating NF-κB-driven inflammatory diseases.