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In this manuscript we report on the design, synthesis and evaluation of dual Sigma 1 Receptor (S1R) modulators/Acetylcholinesterase (AChE) inhibitors endowed with antioxidant and neurotrophic properties, potentially able to counteract neurodegeneration. The compounds based on arylalkylaminoketone scaffold integrate the pharmacophoric elements of RRC-33, a S1R modulator developed by us, donepezil, a well-known AChE inhibitor, and curcumin, a natural antioxidant compound with neuroprotective properties. A small library of compounds was synthesized and preliminary in vitro screening performed. Some compounds showed good S1R binding affinity, selectivity towards S2R and N-Methyl-D-Aspartate (NMDA) receptor, AChE relevant inhibiting activity and are potentially able to bypass the BBB, as predicted by the in silico study. For the hits 10 and 20, the antioxidant profile was assessed in SH-SY5Y human neuroblastoma cell lines by evaluating their protective effect against H2O2 cytotoxicity and reactive oxygen species (ROS) production. Tested compounds resulted effective in decreasing ROS production, thus ameliorating the cellular survival. Moreover, compounds 10 and 20 showed to be effective in promoting the neurite elongation of Dorsal Root Ganglia (DRG), thus demonstrating a promising neurotrophic activity. Of note, the tested compounds did not show any cytotoxic effect at the concentration assayed. Relying on these encouraging results, both compounds will undergo a structure optimization program for the development of therapeutic candidates for neurodegenerative diseases treatment.

Infantile colic can be defined as periods of inconsolable, unexplained, and incessant crying in a seemingly healthy infant that, quite understandably, leads to exhausted, frustrated, and concerned parents seeking to comfort their child (Landgren 2010). The prevalence of excessive crying varies according to the definition used although, most often, it peaks during the second month of life,with a prevalence of 1.5%to 11.9%(Reijneveld 2001).Traditionally, the definition of the condition was based on the rule of three (Wessel 1954): that is, unexplained episodes of paroxysmal crying for more than three hours per day, for three days per week, for at least three weeks. More recently a new definition has been proposed. It refers to a clinical condition of fussing and crying for at least one week in an otherwise healthy infant (Hyman 2006). Colic can be graded as mild, moderate, or severe, though there is no consensus for this classification. Colic can affect up to 10% to 30% of infants worldwide (Clifford 2002; Rosen 2007).