Novel Insights into the Pleiotropic Neuroprotective Action of Synthetic Halogen Free Thyronamine-like Analogues

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 Aβ25–35-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.