Design, synthesis and evaluation of tacrine–flurbiprofen–nitrate trihybrids as novel anti-Alzheimer’s disease agents.

Abstract: 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 Aβ inhibitory effects whereas tacrine and flurbiprofen did not exhibit any Aβ 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. [Copyright &y& Elsevier]