Curcumin-based analogue as multipotent agent against Alzheimer’s disease.

The multifactorial character of Alzheimer’s disease (AD) represents a significant impediment to achieve an effective treatment. A recent new paradigm to treat complex diseases comprises single chemical entities able to concurrently modulate different targets or pathways involved in the pathology (multifunctional compounds). Thus, the multi-target drug discovery approach is gaining ever-increased to obtain effective drug candidates for AD cure[1,2]. A number of features that positively correlate with the severity of the malady include increased release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-15) by activated microglial cells, high levels of Aβ protein and its products of aggregation (soluble Aβ oligomers), together with amyloid fibrils[3]. These neurotoxic mediators trigger a cascade of neurobiological events namely synaptic dysfunctions, astrocytes activation, induction of apoptosis leading ultimately to neuronal cell death. Curcumin (Figure 1), the primary bioactive compound found in the rhizomes of Curcuma longa L., is one of the most thoroughly investigated natural product. Its pleiotropic behaviour is believed to provide the molecular basis of polypharmacology, a relevant aspect implicated in the therapeutic efficacy of drugs[4]. Thus, it could be usefully exploited in the multi-target context. Specifically, curcumin proved to synergistically modulate different AD targets and a wide range of interconnected signalling pathways. In fact, curcumin exerts neuroprotective effects by cytokine suppressive antiinflammatory activity and protection from neurotoxic injuries, such as those derived from Aβ species. Nevertheless, its poor bioavailability and intrinsic neuronal toxicity represents a drawback. In order to develop new disease-modifying drug candidates endowed with a multi-target biological profile, the curcumin scaffold was properly modified. From this study, a compound was identified as valuable anti-AD drug candidate.