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.

The escalating threat of antimicrobial resistance (AMR) compels the development of novel antibiotics with broad spectrum activity and environmentally responsible degradation profiles. Chalcones, naturally occurring 1,3-diaryl-2-propen-1-ones, have emerged as promising scaffolds due to their pleiotropic bioactivity and structural tunability. In this study, we explored the synthesis and functionalization of oxyprenylated chalcones as potential antibacterial compounds and explored their functionalization with protonatable moieties to enhance their affinity for bacterial membranes and their solubility properties. Starting from hydroxycordoin 1a, we synthesized a series of isomeric and hydroxy derivatives, with the aim of studying their structure-activity relationships, and based on the initial results we further modified their structure by including protonatable side chains. A key synthetic step was optimized using a Design of Experiments (DoE) approach, promoting resource efficiency in line with Green Chemistry principles. The antibacterial properties of the synthesized compounds were evaluated in vitro against Gram-positive and Gram-negative strains, and their toxicological profiles and predicted environmental biodegradability were also assessed. These multifunctional chalcone derivatives demonstrate potential as effective and sustainable antimicrobial agents and the benzofuran derivative 20, the most potent compound of the series, could represent an interesting compound for further optmization

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.