Nar_2025_Bioorg.Chem_164_108901

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and cholinergic dysfunction. Given the limitations of current acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors, novel multi-target drug candidates are urgently needed. In this study, a series of DHEA-carbamate derivatives were rationally designed and synthesized to integrate cholinesterase inhibition with potential neuroprotective and pharmacokinetic advantages. The synthesized compounds were characterized via NMR and HRMS, and their inhibitory activities were determined by Ellman's method. While native DHEA displayed negligible cholinesterase inhibition (IC(50) > 75 microM), carbamate derivatization significantly enhanced potency. D1 exhibited the highest AChE selectivity (IC(50) = 0.09 microM, SI = 424), D8 showed the strongest BuChE inhibition (IC(50) = 0.1 microM), and D9 emerged as a dual-action inhibitor (AChE IC(50) = 0.15 microM; BuChE IC(50) = 0.7 microM). Molecular docking supported the observed in vitro activities, particularly the binding affinity of D1 toward AChE (-9.2 kcal/mol). Beyond enzyme inhibition, the most potent compounds (D1, D8, D9) were evaluated for their ability to mitigate H(2)O(2)-induced cytotoxicity in HT-22 neuronal cells. D9 exhibited the strongest protective effect, restoring cell viability up to 78 %. Additionally, the antioxidant activities of D9 were confirmed through DPPH scavenging and ferrous chelation assays, where it again demonstrated superior activity. DNA and HSA interaction studies revealed favorable binding properties, suggesting genomic stability and prolonged systemic availability. ADMET predictions indicated desirable pharmacokinetic profiles, including blood-brain barrier permeability. These results highlight the therapeutic relevance of hybrid steroid-carbamate scaffolds that combine cholinesterase inhibition, antioxidant capacity, and cellular neuroprotection, offering a promising strategy for next-generation AD drug development.