Discovery of novel ibuprofen-1,3,4-thiadiazole derivatives attenuating ulcerative colitis by regulating MAPK-mediated inflammation and restoring intestinal immune homeostasis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising global prevalence that substantially impairs quality of life, yet effective therapeutic options remain limited. Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (IBU) face a therapeutic limitation in UC, as their mechanism exacerbates intestinal injury despite their significant anti-inflammatory efficacy. To overcome this clinical limitation, we designed and synthesized a series of ibuprofen-1,3,4-thiadiazole hybrids (23 compounds in total) and evaluated their anti-inflammatory activities. Notably, compound 20 at 10 mg/kg significantly ameliorated DSS-induced colitis, with efficacy superior to both the parent compound IBU (10 mg/kg) and 5-aminosalicylic acid (5-ASA, 80 mg/kg). Additionally, intervention with compound 20 also restored gut microbiota by modulating gut immunity. Detailed analyses suggested that compound 20 inhibited M1 macrophage polarization and suppressed MAPK-mediated inflammation both in vivo and in vitro. Crucially, compound 20 demonstrated favorable gastrointestinal safety profiles, in contrast to the parent compound IBU. This study underscores the potential clinical relevance of ibuprofen-1,3,4-thiadiazole hybrids as a novel therapeutic strategy for UC with improved gastrointestinal safety profiles.