Design, synthesis and evaluation of tacrine-flurbiprofen-nitrate trihybrids as novel anti-Alzheimer's disease agents
Design, synthesis and evaluation of tacrine-flurbiprofen-nitrate trihybrids as novel anti-Alzheimer's disease agents
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DOI：
10.1016/j.bmc.2013.03.005
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发表时间：
2013-05-01
影响因子：
3.5
通讯作者：
Zhang, Yihua
中科院分区：
文献类型：
--
作者：
Chen, Yao;Sun, Jianfei;Zhang, Yihua
为了寻找安全性好的多功能抗阿尔茨海默病(AD)药物，将先前合成的他克林-氟比洛芬杂化化合物1a和1b修饰为他克林-氟比洛芬-硝酸盐三元杂化化合物3a-h。这些化合物表现出与二价杂化化合物相当或更高的胆碱酯酶抑制活性。化合物3a的作用最强，能释放适量的NO，具有血管松弛活性，并具有显著的Aβ抑制作用，而他克林和氟比洛芬在相同剂量下对抗体无抑制作用。此外，3a还具有改善体内记忆障碍的作用。更重要的是，肝脏毒性研究表明，3a比他克林安全得多，这表明它可能是一种有前途的抗AD药物，用于进一步研究。(C)2013爱思唯尔有限公司。保留所有权利。
To search for multifunctional anti-Alzheimer's disease (AD) agents with good safety, the previously synthesized tacrine-flurbiprofen hybrids 1a and 1b were modified into tacrine-flurbiprofen-nitrate trihybrids 3a-h. These compounds displayed comparable or higher cholinesterase inhibitory activity relative to the bivalent hybrids. Compound 3a was the most potent, which released moderate NO, exerted blood vessel relaxative activity, and showed significant A beta inhibitory effects whereas tacrine and flurbiprofen did not exhibit any Ab inhibitory activity at the same dose. In addition, 3a was active in improving memory impairment in vivo. More importantly, the hepatotoxicity study showed that 3a was much safer than tacrine, suggesting it might be a promising anti-AD agent for further investigation. (C) 2013 Elsevier Ltd. All rights reserved.