A novel core skeleton design and synthesis of N‐alkyl‐1′‐(substituted sulfonyl)spiro[chromene‐2,4′‐piperidin]‐6‐amine derivatives as 5‐lipoxygenase inhibitors

Abstract

Abstract5‐LO inhibitors can potentially be employed for the treatment of various inflammatory disorders. In this study, we have designed and synthesized new N‐alkyl‐1′‐(substituted sulfonyl)spiro[chromene‐2,4′‐piperidin]‐6‐amine‐based library as potential and novel 5‐LO inhibitors. In vitro results showed that several synthesized compounds exhibited high 5‐LO inhibitory activity, in parallel with the inhibition of leukotriene B4 (LTB4) production in the rat basophilic leukemia (RBL‐1) cells. Among the synthesized compounds, 8l was selected for in vivo study using a mouse ear edema model: oral administration of 8l (100 mg/kg) inhibited arachidonic acid‐induced ear edema, myeloperoxidase (MPO) activity, and LTB4 synthesis. SAR analysis and molecular docking studies demonstrated the allosteric binding mode between 5‐LO and the synthesized compounds including 8l.