Butyrylcholinesterase Inhibitors: Structure-Activity Relationships of 2-Phenylbenzofuran derivatives.

Butyrylcholinesterase Inhibitors: Structure-Activity Relationships of 2-Phenylbenzofuran derivatives Antonella Fais1*, Giovanna L. Delogu 1, Benedetta Era 1, Amalia Di Petrillo1, Amit Kumar2,3, Paola Caria4, Sonia Floris1, Francesca Pintus1 1Department of Life and Environmental Sciences, University of Cagliari , Cagliari , Italy; 2Department of Mech., Chem. and Material Engineering , University of Cagliari , Cagliari , Italy; 3Biosciences Sector, CRS4 ,Pula , Italy 4Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy *Corresponding author: fais@unica.it Alzheimer’s disease (AD) is an irreversible and progressive brain disorder which is characterized by progressive memory loss and a wide range of cognitive impairments.1 Although the precise cause of AD is not completely known, there are some factors that seem to play a significant role in the pathogenesis of AD. Since AD is characterized by a forebrain cholinergic neuron loss and a progressive decline in acetylcholine, a possible therapeutic strategy involves the use of cholinesterase (ChE) inhibitors to restore the neurotransmitter level and thus alleviate AD symptoms.2 Benzofuran scaffold has drawn considerable attention over the last few years due to its profound physiological and chemotherapeutic properties. Recent studies have also investigated their inhibitory activity towards ChEs.3,4 In this study, a series of 2-phenylbezonfurans compounds were synthesized and their inhibition activity towards the ChE enzymes were investigated. We further combined biochemical analysis and molecular modelling studies to identify selective butyrylcholinesterase (BChE) inhibition by benzofuran scaffold. In particular, two compounds exhibited the highest BChE inhibition with IC50 values better than the standard cholinesterase inhibitor compound. Molecular modelling studies highlighted the importance of catalytic and peripheral site residues in BChE inhibition. Subsequently, the biosafety of the two promising compounds was evaluated, in NSC-34 cells at the concentration in which BChE activity is inhibited, and no considerable cytotoxic effect was found. References 1. Schuster et al. Bioorg. Med. Chem. (2010) 18, 5071. 2. Zemek et al. Expert Opin Drug Saf (2014) 13, 759. 3. Mostofi et al. Eur. J. Med. Chem. (2015) 103, 361. 4. Delogu et al. Bioorg. Med. Chem. (2016) 26, 2308.