Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX

In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50= 0.23 +/- 0.16 mu M for COX-2, IC50 = 0.87 +/- 0.07 mu M for 5-LOX, IC50 = 4.48 +/- 0.57 mu M against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50 = 0.41 +/- 0.28 mu M for COX-2, IC50 = 7.68 +/- 0.55 mu M against A549) and Zileuton (IC50 = 1.35 +/- 0.24 mu M for 5-LOX). Further investigation confirmed that 11g could induce human non small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents. (C) 2017 Elsevier Ltd. All rights reserved.