title: Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease.
abstract: 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.
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Chimica Biomolecolare (ICB), Pozzuoli, NA, Italy. Electronic address: gtommonaro@icb.cnr.it.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Tommonaro
authors.affiliation: Universidad Complutense de Madrid, Facultad de Farmacia, Dpto. de Bioquímica y Biología Molecular II, Spain. Electronic address: nurilen_12@hotmail.com.
authors.forename: Nuria
authors.initials: N
authors.lastname: García-Font
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Chimica Biomolecolare (ICB), Pozzuoli, NA, Italy. Electronic address: rmvitale@icb.cnr.it.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Vitale
authors.affiliation: University of Belgrade, Department of Life Sciences, Institute for Multidisciplinary Research - IMSI, Belgrade, Serbia. Electronic address: brspjn@gmail.com.
authors.forename: Boris
authors.initials: B
authors.lastname: Pejin
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Chimica Biomolecolare (ICB), Pozzuoli, NA, Italy. Electronic address: ciodice@icb.cnr.it.
authors.forename: Carmine
authors.initials: C
authors.lastname: Iodice
authors.affiliation: Universidad Complutense de Madrid, Facultad de Farmacia, Dpto. de Bioquímica y Biología Molecular II, Spain. Electronic address: sicada@ucm.es.
authors.forename: Sixta
authors.initials: S
authors.lastname: Cañadas
authors.affiliation: Laboratory of Medicinal Chemistry (IQOG, CSIC), Madrid, Spain. Electronic address: jlmarco@iqog.csic.es.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Universidad Complutense de Madrid, Facultad de Farmacia, Dpto. de Bioquímica y Biología Molecular II, Spain. Electronic address: mjoset@ucm.es.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Oset-Gasque
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D004593:Electrophorus; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011487:Protein Conformation; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D012717:Sesquiterpenes; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C023663:avarol
keywords: Alzheimer’s disease; Anticholinesterasic compounds; Avarol; Molecular modeling; Neuroprotection; Thiosalycil-prenyl-hydroquinones (TPHs)