Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer’s disease

• Avarol-3′-thiosalicylate and thiosalycil-prenylhydroquinones (TPHs) have been synthesized.
• The AChE and BuChE enzymatic and neuroprotective activities of compounds TPH1-5 are described.
• TPH4 is the most potent AChE and BuChE inhibitor.
• TPH4 is non-hepatotoxic and the best neuroprotector among TPHs compounds.

Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects. Due to the complex nature of Alzheimer’s disease (AD), there is a renewed search for new, non hepatotoxic anticholinesterasic compounds. This paper describes the synthesis and in vitro biological evaluation of avarol-3′-thiosalicylate (TAVA) and thiosalycil-prenyl-hydroquinones (TPHs), as non hepatotoxic anticholinesterasic agents, showing a good neuroprotective effect on the decreased viability of SHSY5Y human neuroblastoma cells induced by oligomycin A/rotenone and okadaic acid. A molecular modeling study was also undertaken on the most promising molecules within the series to elucidate their AChE binding modes and in particular the role played by the carboxylate group in enzyme inhibition. Among them, TPH4, bearing a geranylgeraniol substituent, is the most significant Electrophorus electricus AChE (EeAChE) inhibitor (IC50 = 6.77 ± 0.24 μM), also endowed with a moderate serum horse butyrylcholinesterase (eqBuChE) inhibitory activity, being also the least hepatotoxic and the best neuroprotective compound of the series. Thus, TPHs represents a new family of synthetic compounds, chemically related to the natural compound avarol, which has been discovered for the potential treatment of AD. Findings prove the relevance of TPHs as a new possible generation of competitive AChE inhibitors pointing out the importance of the salycilic substituents on the hydroquinone ring. Since these compounds do not belong to the class of alkaloids, which are notorious for their capability to inhibit AChE while exhibiting side effects, they may constitute novel active AChE inhibitors with fewer side effects.

TPHs represent a new family of synthetic compounds, chemically related to the natural compound Avarol, which has been discovered for the potential treatment of AD. Among them, TPH 4, bearing a geranylgeraniol substituent, is the most significant AChE and BuChE inhibitor, non-hepatotoxic and the best neuroprotective compound against oxidative stress and Tau Phosphorylation.Figure optionsDownload as PowerPoint slide