A novel core skeleton design and synthesis of N-alkyl-1'-(substituted sulfonyl)spirochromene 2,4 piperidin-6-amine derivatives as 5-lipoxygenase inhibitors

摘要

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)spirochromene-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,8I was selected for in vivo study using a mouse ear edema model:oral administration of 8I(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 8I.