Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase.
Dual function inhibitors targeting phospholipase A(2) (PLA(2)) and leukotriene A(4) hydrolase (LTA(4)H) 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 A(2) (hnps-PLA(2)) and human leukotriene A(4) hydrolase (LTA(4)H-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-PLA(2) and LTA(4)H-h with IC(50) values of 9.2 ± 0.5 μM and 2.4 ± 1.4 μM, respectively.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-Y
human leukotriene A(4) hydrolase LTA(4)H-h PLA(2) leukotriene A(4) hydrolase hnps-PLA(2) LTA(4)H-h LTA(4)H phospholipase A2 leukotriene A4 hydrolase arachidonic acid JMC08-4 JMC08-4 5-hydroxytryptamine JMC08-4 5-hydroxytryptamines human nonpancreatic secretory phospholipase A(2) phospholipase A(2) hnps-PLA(2)