Design and synthesis of a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for the potential treatment of COPD

It is well known that chronic obstructive pulmonary disease (COPD) patients are always trapped in the vicious circle of inflammation and oxidative stress, therefore anti-inflammatory and antioxidant bifunctional agents interrupt this vicious cycle in COPD. Phosphodiesterase 4 (PDE4) inhibitors, as anti-inflammatory drugs, been used for COPD treatment in clinical, and the PDE4 inhibitors with antioxidant properties may be a strategy to design bifunctional agents for COPD. Sappanone A was the first PDE4 inhibitor with antioxidant properties we identified from natural products in our previous study, which was used by us as a hit compound design new bifunctional agents for COPD in this study. 27 derivatives of sappanone A including homoiso-flavonoids, aurones and chalcones were designed and synthesized by innovatively fusing the antioxidant macophore of catechol from polyphenols and the pharmacophore of catechol ether abstracted from the PDE4 inhibitors of the catechol ether class such as rolipram, roflumilast and apremilast respectively. All the compounds were assayed for the PDE4 inhibitory and radical scavenging against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) activities in vitro. Herein we obtained a series of bifunctional compounds with better PDE4 inhibitory activity than sappanone A, and their free radical scavenging activities were superior to edaravone in vitro. In addition, they can reduce tumour necrosis factor-alpha (TNF-alpha) production induced by lipopolysaccharide (LPS) RAW264.7 macrophages and malondialdehyde (MDA) production induced by Fe2+ in mouse lung homogenate. Meanwhile, it showed outstanding abilities in reducing Fe3+ and complexing Fe2+. 6o, as the candidate inflammatory and antioxidant bifunctional compound, exhibited good drug-likeness, ADME (Absorption, tribution, Metabolism, Excretion) properties and human liver microsomal stability. In vivo, 6o (50 mg/kg 100 mg/kg, i. p.) distinctly prevented LPS-induced serum levels of TNF-alpha in mice. In conclusion, the preliminary investigation provided a novel class of PDE4 inhibitors with antioxidant properties as bifunctional agents for potential treatment of COPD, which can interrupt the vicious cycle of chronic inflammation and oxidative stress in COPD.