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In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca 2+ levels. A dysregulation of the mitochondrial Ca 2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na + /Ca 2+ exchanger (NCLX) is the principal efflux pathway of Ca 2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca 2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca 2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.

In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ 1 R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N -(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4 H -chromene-2-carboxamide ( 18 ) is highlighted due to its interesting biological profile in σ 1 R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and σ 1 R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs. [ABSTRACT FROM AUTHOR]