Hybrid molecules phenothiazine/cinnamic derivatives as MTDL and their biological evaluation

In order to identify new classes of drugs with neuroprotective effect useful for the treatment of neurodegenerative diseases, and in particular Alzheimer's disease (AD), our research project aims to design and synthesize new hybrid molecules using the fragment-based strategy to obtain multitarget directed ligands (MTDL). For this purpose, we combined the phenothiazine scaffold with a naturally occurring substituted-cinnamic acid with antioxidant properties, hoping for a synergistic effect. In fact, neurodegenerative diseases are characterized by extensive intracellular oxidative damage that can lead to cell death, worsening the disease prognosis. Furthermore, the phenothiazine scaffold is already used in clinical practice as antidepressants or antipsychotics, demonstrating the capacity to bypass the blood-brain barrier (BBB) and a relative safety. Pursuing our research, we obtained a small library of compounds through a multistep synthesis with good yields. All compounds have been tested for their activity on the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) showed IC50 values in the low micromolar range. Additionally, the antioxidant activity of new compounds was determined by colourimetric DPPH assay. The more interesting compounds have been tested in vitro for their direct inhibitory activity against β-amyloid aggregation. Based on the results obtained, it was possible to establish a structure-activity relationship (SAR) to obtain new inhibitors with activity on both cholinesterase or selective for AChE/BChE. Furthermore, the compounds with the best activity will be studied for their antioxidant and neuroprotective activity in cells and for their ability to prevent cell damage caused by aggregates of the β-amyloid protein.