Jiang_2011_Bioorg.Med.Chem_19_7228

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 beta (Abeta) aggregation; and (iii) antioxidant activity. All of the derivatives were better antioxidants, and inhibited Abeta 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 0.374 muM); and the berberine-hydroquinone hybrid (compound 12) displayed high antioxidant activity, could inhibit AChE (IC(50) of 0.460 muM), and had the greatest ability to inhibit Abeta aggregation.