Enzymatic and solid-phase synthesis of new donepezil-based L- and D-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia

Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.ejmech.2017.02. 034. These data include MOL files and InChiKeys of the most important compounds described in this article.Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds.This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO, grants SAF2015-64948-C2-1-R and SAF2012-31035) and Consejo Superior de Investigaciones Científicas (CSIC, grant PIE-201580E109) to M.I.R.-F; Instituto de Salud Carlos III (Miguel Servet contract and projects CP11/00165 and PI14/00372), European Commission - Marie Curie Actions FP7 (FP7- People-2012-CIG-322156), Bayer AG, From Targets to Drugs (grant 2015-03-1282) and Fundacion FIPSE (grant 12-00001344-15) to R.L.; Spanish Ministry of Economy and Competitiveness (SAF2015- 63935) to M.G.L.; and Spanish Ministry of Education (fellowship for Master Studies) to L.M.Peer Reviewe