Novel multi-targeted anti-Alzheimer’s ligands from marine sources

Alzheimer’s disease (AD), one of the most common cause of dementia in elderly population, is a complex neuro-degenerative disorder of the central nervous system. It is characterized by a progressive and irreversible degeneration of cholinergic neurons with the concomitant decrease of the hippocampal and cortical neurotransmitter acetylcholine (Ach) levels, and by the presence of amyloid plaques and neurofibrillary tangles. The current pharmacological therapy for AD is mainly based on acetylcholinesterase inhibitors (AChEI), aimed at restoring the Ach tone in the brain. However, due to the multifactorial aetiology of this pathology, compounds able to act simultaneously on two or more relevant biological targets are high desirable. In this study, the combination of AChE inhibition with the impairment of β-amyloid peptide's aggregation and deposition by inhibition of β-secretase enzyme (BACE- 1), is approached. The previous identification of a pseudozoanthoxanthin variant from the zoanthid crust coral Parazoanthus axinellae, as an acetylcholinesterase inhibitor prompted us to search other molecules sharing a similar scaffold in our collection of natural marine compounds, and to explore the potentiality of the newly- selected molecules as multiligand agents, by including as potential target BACE-1 and investigating the ability of this scaffold to inhibit β-amyloid aggregation. The most similar compounds among those available in suitable quantities for subsequent experimental validation within our collection were a pseudo- zoanthoxanthin from an unidentified caribbean zoanthid (CUNC2), differing from the analog reported in the literature for the number and position of methyl substituents on the azulene ring, and the bromo-pyrrole alkaloid stevensine (STEV). Docking and molecular dynamics studies were carried out on both AChE and BACE-1 enzymes as well as on β-amiloid fibrils. The positive results obtained in silico were then confirmed by biochemical assays that showed an inhibition for both enzymes in the low/sub-micromolar range.