Development of Dithioacetal‐Modified Dihydropyrimidone Derivatives with Potential Anti‐Inflammatory Activity for Inflammatory Bowel Disease

ABSTRACT

Inflammatory bowel disease (IBD) is a chronic autoimmune disorder, and the development of novel anti‐inflammatory small molecules is crucial for advancing therapeutic options. In this study, we designed and synthesized a series of novel dihydropyrimidinone derivatives containing dithioacetal groups. Through in vitro safety assessments and anti‐inflammatory screening, we identified several compounds with promising biological activities. Notably, compound D3 exhibited exceptional anti‐inflammatory effects, demonstrating an IC ₅₀ of 1.2 µM in inhibiting NO secretion. Mechanistic investigations revealed that D3 inhibits the activation of the MAPK/NF‐κB signaling pathway, thereby reducing the expression of LPS induced pro‐inflammatory proteins and the secretion of NO. In vivo, compound D3 effectively ameliorated DSS‐induced acute colitis in mice, as evidenced by reductions in body weight loss and colonic adhesion. In conclusion, we have developed a series of promising anti‐inflammatory small molecules that may offer significant therapeutic potential for IBD and contribute to the development of new anti‐inflammatory drugs.