Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A(2) and leukotriene A(4) 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 IC50 values of 9.2 +/- 0.5 mu M and 2.4 +/- 1.4 mu M, respectively. (C) 2012 Elsevier Masson SAS. All rights reserved.Chemistry, MedicinalSCI(E)PubMed0ARTICLE160-1675