Design and synthesis of novel curcumin derivatives as potent PDE4 inhibitors for the treatment of depression

PDE4 is a potential target for treating mental diseases including depression, Alzheimer's disease and schizophrenia involving in the hydrolysis of cAMP. Curcumin is well-known for its potential as a neuroprotective compound against depression. It was able to inhibit PDE4 with IC50 value in the range of 10 to 20 mu M with low selectivity. However, curcumin itself cannot be used clinically because of its poor drug-like properties. Herein, a series of new curcumin derivatives were designed and synthesized. Their PDE4 inhibitory activities and antidepressant effects in vivo were also evaluated. Consequently, most of these curcumin derivatives demonstrated good inhibitory activities against PDE4. Furthermore, compound 4e exhibited the most potent activity at nanomolar level (IC50 value: 23 nM). It also could improve depression-like behaviors induced by chronic stress including sugar forced swimming and water consumption tests in vivo.