| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1394392 | European Journal of Medicinal Chemistry | 2013 | 8 Pages |
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 full-size imageDownload 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.
