AbstractBackgroundAlzheimer’s Disease (AD) is a progressive neurodegenerative disturb that has reached global epidemic proportions. As a complex multifactorial disease affecting different cells in CNS, and with no effective treatment, developing new neuroprotective agents is critical (Therriault, J. et al, 2022). Based on that, a series of innovative molecules based on chalcones of natural origin was developed. Their cytotoxicity and neuroprotective effects were evaluated in silico and in vitro experimental platforms. Flavonoid derivatives are known for their anti‐inflammatory and antioxidant potential in AD (DAS, S. et al, 2017), however, there are few studies relating the action of the flavonoids' precursors called chalconoids (GOMES, M.N. et al., 2017).MethodThe research was carried out in two stages. The first stage was performed in silico, where virtual platforms were used to determine and predict the drug‐like characteristics of compounds and their ability to permeate by the blood‐brain barrier (BBB). The second stage evaluated the in vitro cytotoxicity in healthy cell lines (Vero and C6) and the neuroprotective effect against glutamatergic and oxidative insults in astroglial cells. In addition, the in vitro evaluation of cell viability was carried out using colorimetric methods (SRB and MTT). The neuroprotector effect was evaluated after pre‐exposure of cells to molecules under study.ResultRegarding the tested compounds, nineteen in the series presented adequate drug‐like properties and low or no cytotoxicity. Among them, three showed significant neuroprotective potential against both insults (oxidative stress and glutamatergic excitotoxicity) in astroglial cells, keeping the cell viability between 70% and 80%. In addition, these compounds have a high potential to cross the BBB and will proceed to the in vivo pre‐clinical studies phase.ConclusionThe designed chalconoids showed low cytotoxic potential and chemical characteristics compatible with oral use and passage through BBB. These results suggest chalcone derivatives as promising multi‐target agents preventing AD.