Alzheimer's disease (AD), affecting 47 million people worldwide, is regarded as the most prevalent neurological disorder and represents a significant health and social challenge. It involves various pathological events, including the CNS accumulation of β-amyloid protein (Aβ) aggregates, which trigger a cascade of toxic events such as oxidative stress, inflammatory response, and mitochondrial dysfunction. These effects are interconnected in a feed-forward loop that eventually causes synaptic degeneration and neuronal cell death. The nuclear factor erythroid 2-related factor 2 (Nrf2), activated in response to oxidative stress and neuroinflammation, induces the transcription of antioxidant genes and promotes the expression of several cytoprotective genes1. In this scenario, the concurrent modulation of different misregulated targets in AD offers a promising therapeutic approach to tackle this multifaceted disease. Chalcones (1,3-diaryl-2-propen-1-ones), prominent secondary metabolites and precursors of flavonoids, exhibit a wide range of bioactivities, including the ability to modulate various crucial targets involved in neurodegenerative diseases. Thus, the chalcone scaffold can be considered a promising and versatile chemical platform for obtaining multifunctional anti-AD agents2. In this context, two series of chalcone-based hybrid molecules were designed, in an effort to obtain analogues with extended anti-AD potential, modulating neuroinflammatory and oxidative stress responses. Series A: Chalcone-glypromate (GPE) conjugates. GPE is an endogenous tri-peptide (glutamic acid-proline-glycine) that has gained attention for its significant neuroprotective potential3. These hybrids were developed by connecting, through an acetoxy spacer, the chalcone core with different fragments related to GPE. Series B: Chalcone-triazole conjugates. In these analogues, the 1,2,3-triazole heterocycle, decorated with an ethyl ester moiety, was introduced since the presence of this fragment has granted neuroprotective activity to previously developed compounds1 (Figure 1). Figure 1 . Design strategy for Series A and B of chalcone-based hybrids. For the designed derivatives, the ability to counteract oxidative stress and neuroinflammation was determined. REFERENCES 1 De Lorenzi, E., Seghetti, F., Tarozzi, A., Pruccoli, L., Contardi, C., Serra, M., Bisi, A., Gobbi, S., Vistoli, G., Gervasoni, S., Argentini, C., Ghirardo, G., Guarato, G., Orso, G., Belluti, F., Di Martino, R. M. C., & Zusso, M. (2023). Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold. European Journal of Medicinal Chemistry, 252, 115297. 2 Thapa, P., Upadhyay, S. P., Suo, W. Z., Singh, V., Gurung, P., Lee, E. S., Sharma, R., & Sharma, M. (2021). Chalcone and its analogs: Therapeutic and diagnostic applications in Alzheimer's disease. Bioorganic Chemistry, 108, 104681. 3 Sampaio-Dias, I. E., Santejo, M., Silva-Reis, S. C., Liz, M. A., Alcoholado, C., Algarra, M., García-Mera, X., & Rodríguez-Borges, J. E. (2021). Design, synthesis, and biological evaluation of hybrid glypromate analogues using 2-azanorbornane as a prolyl and pipecolyl surrogate. ACS Chemical Neuroscience, 12(19), 3615–3624.
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