Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder involving metabolic impairment, neuroinflammation, synaptic failure, and comorbidities. Hence, therapeutic development for AD is rapidly shifting from a single-target approach, centred on amyloid-beta (Aβ) reduction, to multi-target strategies. In this study, we investigated the neuroprotective profile of two acetanilide derivatives, SG-22 and SG-23, originated from the halogen-free thyronamine-like lead compound SG-2. Their efficacy was evaluated through an integrated approach combining in vitro cellular models, in vivo phenotypic screening in a Caenorhabditis elegans AD model, and comprehensive ADME-Tox profiling. In U87MG cells, both SG-22 and SG-23 effectively prevented Aβ_25–35-induced cytotoxicity and restored autophagy-related gene expression, including LC3, SIRT1, and SIRT6, while reducing mTOR and SIRT5 levels. Furthermore, all compounds exhibited anti-inflammatory effects in activated HMC3 microglial cells, reducing IL-6 and increasing IL-10 levels, with evidence suggesting partial involvement of TAAR1 signalling. ADME-Tox analyses revealed improved safety and metabolic profiles for the tested compounds, particularly SG-22, which showed reduced hERG liability and enhanced cytochrome P450 stability. However, in vivo studies demonstrated that only SG-2 and SG-23 improved motility and fitness in the C. elegans AD model, consistent with their ability to activate autophagy, whereas SG-22 was ineffective due to limited organismal uptake. Ultimately, the monoacetylated analogue SG-23 emerges as a promising candidate, balancing neuroprotective efficacy and drug-like properties, and supporting thyronamine-like analogues as multi-target agents for AD.

Background: Pomegranate peel, a major by-product of the food industry, represents an underexploited source of valuable bioactive compounds. In the framework of a circular economy approach, this study aimed to develop a sustainable and solvent-free extraction strategy based on Saccharomyces cerevisiae fermentation for the recovery of antioxidant and antimicrobial phytochemicals from pomegranate peel waste. Methods: Pomegranate peel was subjected to fermentation for 18, 24, 48, and 72 h, and the resulting extracts (YE_18h, YE_24h, YE_48h, and YE_72h), together with a conventionally obtained chemical extract (CE), were evaluated for their antioxidant activity. Based on its superior antioxidant activity, the extract obtained after 48 h of fermentation (YE_48h) was selected for ellagic acid quantification by HPLC and characterization by UHPLC-HRMS (Ultra-High-Performance Liquid Chromatography coupled to High-Resolution Mass Spectrometry). Antibacterial activity of YE_48h, in comparison with CE, was assessed against six Gram-positive and Gram-negative bacterial strains. Results: Among the fermented samples, the extract obtained after 48 h of fermentation (YE_48h) exhibited the highest antioxidant activity, showing an IC₅₀ value lower than that of a conventional chemical extract. Quantitative HPLC analysis revealed a remarkable enhancement in ellagic acid content, with YE_48h containing approximately 18-fold higher levels of ellagic acid than the conventional chemical extraction. UHPLC-HRMS fingerprinting further demonstrated the presence of additional bioactive phenolic compounds, including punicalagin isomers I and II and pedunculagin isomer I, which are known for their antioxidant and antimicrobial properties. The antibacterial assay demonstrated that fermentation modulated the antimicrobial profile of the extracts in a strain-dependent manner. Conclusions: S. cerevisiae-mediated fermentation is an efficient and environmentally friendly approach for the valorization of pomegranate peel by-products, enhancing the release of bioactive compounds while generating extracts with promising antioxidant and selective antibacterial properties.