Natural-product-inspired modulators of Alzheimer’s disease: focus on amyloid and oxidative stress

Alzheimer’s disease (AD) is a multifactorial syndrome, with a complex interplay of genetic and biochemical factors contributing to the pathological decline. Besides diffuse neuronal loss, AD brain exhibits evidence of protein folding defects. There is considerable evidence that amyloid-beta peptide (Abeta) might trigger the disease process, and an increasing number of molecular targets, that may play an important role in the expression of its neurotoxicity, is emerging. In particular, the etiopathogenic loop generated by Abeta and oxidative stress indicates ROS overproduction as a crucial partner of Abeta toxicity. Natural products offer a great structural diversity, and have already proven to be a rich source of therapeutics. Curcumin is a natural polyphenol that modulates several AD pathways, including oxidative injuries and Abeta aggregation. The active principle of garlic diallyl disulfide is able to counteract oxidative stress through antioxidant enzyme expression. These structures inspired us to design new chemical entities carrying the cinnamoyl function of the former and the allyl mercaptan moiety of the latter. Interestingly, most of the synthesized hybrids demonstrated to be less toxic than curcumin in different cell lines. In addition, modifications of the aryl substitution pattern allowed to modulate the antioxidant profile, and identify the derivative bearing the catechol moiety as an intriguing anti-aggregating agent. Thus, we obtained promising pharmacologic tools, which offer the chance to gain insight into the AD cross-talk between Abeta and radical species.