Anti-inflammatory agents design via the fragment hybrid strategy in the discovery of compound c1 for treating ALI and UC

Abstract

Acute lung injury (ALI) and ulcerative colitis (UC) are common inflammatory diseases with high mortality rates and unsatisfactory cure rates. Studies have indicated that inhibiting the expression and release of inflammatory factors holds potential for the treatment of inflammatory diseases. In this study, we designed and synthesized 28 derivatives of 6,7-disubstituted-4-cis-cyclohexanequinazoline and assessed their anti-inflammatory activities in mouse macrophages RAW264.7, J774A.1, and human monocyte THP-1 cell lines. Among them, derivative c1 was found to significantly inhibit the expression and release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) induced by lipopolysaccharide (LPS) in the three cells mentioned above. It was also demonstrated that c1 could bind to IRAK4 and affect the expression of these two inflammatory factors by inhibiting the activation of the MAPK pathway. Furthermore, in vivo experiments revealed that c1 effectively ameliorated LPS-induced ALI and dextran sulfate sodium (DSS)-induced UC. Additionally, we evaluated the pharmacokinetic properties and in vivo safety of c1. Therefore, our research has identified the 6,7-disubstituted-4-cis-cyclohexanequinazoline derivative c1 exhibiting promising anti-inflammatory effects as a prospective anti-inflammatory drug candidate.