Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease

Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and only few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) have been pointed out as relevant in AD. work, explored structural modifications well-established I2-IR ligands, giving access derivatives an imidazole-linked heterocycle common key feature. We report synthesis, affinity human I2-IRs, brain penetration capabilities, silico ADMET studies, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies new bunch ligands. Selected compounds showed neuroprotective properties beneficial effects vitro model Parkinson’s disease, rescued dopaminergic cell line SH-SY5Y from death after treatment 6-hydroxydopamine, crucial anti-inflammatory cellular neuroinflammation. After preliminary pharmacokinetic study, action our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 mouse AD (5xFAD). Oral administration at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment synaptic plasticity, well reduced neuroinflammation markers. summary, ligand promoted should be considered promising strategy neurodegeneration.