Design, Synthesis, and Evaluation of Multitarget-Directed Resveratrol Derivatives for the Treatment of Alzheimer's Disease

A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced beta-amyloid (A beta) aggregation and Cu(II)-induced A beta(1-42) aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds 5d and 10d are potential lead compounds for AD therapy (5d, IC50 = 7.56 mu M and 10d, IC50 = 6.51 mu M for self-induced A beta aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured A beta fibrils generated by self- and Cu(II)-induced A beta aggregation. Furthermore, 5d crossed the blood-brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that 5d is a very promising lead compound for AD.