Design And Synthesis Of PDE4/Tubulin And PDE4/AChE Dual Target Inhibitors

Cyclic adenosine monophosphate(cAMP)is involved in many physiological processes,such as the genesis and progression of tumors,and the cognitive and memory function,etc.Many studies have confirmed that PDE4,cAMP-specific hydrolyzing enzymes,is a important target for the treatment of tumors and Alzheimer’s disease(AD).However,the pathogenesis of both tumors and Alzheimer’s disease is very complex.Therefore,single-target drugs aren’t sufficiently effective for the complexity of intractable diseases,such as neurodegenerative diseases and cancer.In contrast to a single target model,multifunctional molecules can combat several pathological features simultaneously.To discover novel multifunctional molecules with with good efficacy,novel PDE4/Tubulin and PDE4/AChE dual target inhibitors were designed and synthesized by combining the structural characteristics of phosphodiesterase IV inhibitors and the structures of Tubulin or acetylcholinesterase inhibitors respectively,and investigated for their activities.Part One:Discovery of novel trim ethoxy phenylbenzo[d]oxazoles as dual tubulin/PDE4 inhibitorsTo discover PDE4/tubulin dual inhibitors with novel skeleton,twenty-seven novel trimethoxyphenylbennzo[d]oxazoles were designed by migrating the trimethoxyphenyl group of TH03 to benzo[d]oxazole moiety.Among these compounds,about half of them displayed good antiproliferative activities against U251,A549 and H460 cell lines.Structure-activity relationships of them led to the identification of novel 3,4,5-trimethoxyphenylbenzo[d]oxazole bearing lH-Indol-5-yl side-chain as dual PDE4/tubulin inhibitor,which displayed less potency against U251 cell lines(IC50 =300 ± 50 nM)than CA-4,but more potency against A549(IC50 = 55 ± 6 nM)and H460(IC50 = 24 ± 2 nM)cell lines than CA-4.Further investigations revealed Zlr induced apoptosis at G2/M phase arrest in glioma and lung cancer cells,and disrupted the microtubules network.The preliminaiy mechanism of action showed that Zlr down-regulated the expression of Cyclin B1 and its upstream regulator gene CDC25c in A549.Part two: Discovery of novel indanonc ether-based dual PDE4/AChE inhibitors Catechol ether moiety can simulate the hydrophobic properties of cAMP,thus,has been used in many PDE4 inhibitors as a key active scaffold.Catechol ether-based AChE inhibitor donepezil displayed weak inhibitory activity against PDE4(IC50=36.0μM).Based on these results,32 catechol ether-based dual PDE4/AChE inhibitors were designed and synthesized in this pait,using donepezil as a lead compound.Among these compounds,compounds Z2a-f bearing a(1-Benzylpiperidin-4-yl)methyl group dispalyed good inhibitory activites toward AChE(0.045μM < IC50 < 0.81μM),but no activities toward PDE4.Replaceing(l-benzylpiperidin-4-yl)methyl group with a pyridin-3-ylmethylene group(as shown in the following figure),Z2 p displayed good PDE4D7 inhibitor activity,which is about 10-fold over that of donepezil.But the inhibitory activity against acetylcholinesterase of Z2p is lower.It’s amazing that the repalcement of a pyridin-3-ylmethylene group and cyclopentyloxy groups in Z2 p with pyridin-3-ylmethyl and 2-(piperidin-l-yl)ethoxy groups,the inhibitor activity against AChE and PDE4 was significantly enhanced.Compared with Z2 P,Z2C showed a nearly 30-fold higher AChE inhibitory activity(IC50 = 0.28 ± 0.10 μM).Compared with donepezil,the AChE inhibitory activity of Z2 C was slightly decreased,but the PDE4 inhibitory activity of Z2C(IC50 = 1.88 ±0.08μM)was significantly increased by about 19 times.Further mechanism study showed Z2 C displayed good inhibitory activity against TNF-α in BV-2 cells at tlie concentration of 10μM,and inhibitory activity against acetylcholinesterase in the rat brain.