Bioorg Med Chem. 2011 Oct 8. [Epub ahead of print] Benzenediol-berberine hybrids: Multifunctional agents for Alzheimer's disease.
Institute of Chemical Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, People's Republic of China; The Industrial Institute of Fine Chemicals and Synthetic Drugs, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
We designed and synthesized a series of hybrid molecules, in an effort to identify novel multifunctional drug candidates for Alzheimer's disease (AD), by reacting berberine with benzenediol, melatonin, and ferulic acid. The products were evaluated for: (i) the ability to inhibit multiple cholinesterases (ChEs); (ii) the capacity to prevent amyloid β (Aβ) aggregation; and (iii) antioxidant activity. All of the derivatives were better antioxidants, and inhibited Aβ aggregation to a greater extent, than the lead compound, berberine. Two of the hybrids, in particular, have the potential to be excellent candidates for AD therapy: the berberine-pyrocatechol hybrid (compound 8) was a much better inhibitor of acetylcholinesterase (AChE) than unconjugated berberine (IC(50): 0.123 vs 0.374μM); and the berberine-hydroquinone hybrid (compound 12) displayed high antioxidant activity, could inhibit AChE (IC(50) of 0.460μM), and had the greatest ability to inhibit Aβ aggregation.
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