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

초록

5-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.

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