Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase

Dual function inhibitors targeting phospholipase A2 (PLA2) and leukotriene A4 hydrolase (LTA4H) may balance the arachidonic acid (AA) metabolic network and be used as new anti-inflammatory drugs. In previous study, we discovered multi-target drugs towards the AA metabolic network, among which a dual-target inhibitor (JMC08-4) for human nonpancreatic secretory phospholipase A2 (hnps-PLA2) and human leukotriene A4 hydrolase (LTA4H-h) was found. Based on the structure of compound JMC08-4, new dual-target inhibitors were designed assisted by molecular docking. In this report, a series of 5-hydroxytryptamine compounds were synthesized; and most of these title compounds showed more potent inhibitory activity than compound JMC08-4 in the in vitro bioassay against these two enzymes. The best one inhibited hnps-PLA2 and LTA4H-h with IC50 values of 9.2 ± 0.5 μM and 2.4 ± 1.4 μM, respectively.

Graphical Abstract5-Hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase.Figure optionsDownload as PowerPoint slideHighlights
► 5-HT derivatives were designed and synthesized as PLA2/LTA4H dual inhibitors.
► Inhibitory activities of synthesized compounds were evaluated in vitro.
► Most compounds showed more potent inhibition than template compound JMC08-4.
► Compound 5f showed the highest activity against LTA4H-h and hnps-PLA2.
► 5-HT derivatives serve as potential leads for further dual inhibitors study.