Design, synthesis and anti-inflammatory evaluation of arylamide-modified pyrrolo[2,3-d]pyrimidine derivatives against acute lung injury.

Abstract

Acute lung injury (ALI) is a severe inflammatory disorder for which effective therapeutic options remain limited. In this study, a series of novel pyrrolo[2,3-d]pyrimidine derivatives bearing amide or sulfonamide moieties were synthesized and evaluated for their anti-inflammatory activities. Structure-activity relationship (SAR) analysis identified compound B19 as exhibiting potent inhibitory effects on IL-6 and IL-8 production in LPS-stimulated HBE, THP-1, and RAW 264.7 cells while showing low cytotoxicity. Mechanistic studies indicated that the anti-inflammatory effects of compound B19 are associated with the simultaneous modulation of the NF-κB and MAPK signaling pathways. In an LPS-induced mouse model of ALI, treatment with compound B19 significantly alleviated pulmonary inflammation and edema, attenuated inflammatory cell infiltration, and markedly decreased pro-inflammatory cytokine levels in bronchoalveolar lavage fluid. These findings highlight compound B19 as a promising candidate for the treatment of ALI and provide a solid foundation for the further development of pyrrolo[2,3-d]pyrimidine-based anti-inflammatory agents.