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±0.16μM for COX-2, IC₅₀=0.87±0.07μM for 5-LOX, IC₅₀=4.48±0.57μM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC₅₀=0.41±0.28μM for COX-2, IC₅₀=7.68±0.55μM against A549) and Zileuton (IC₅₀=1.35±0.24μM 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.

5-LOX; COX-2; Cancer; Coumarin; Pyrazole.