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

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 IC50 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.