Design, Synthesis, and Pharmacological Evaluation of Embelin–Aryl/alkyl Amine Hybrids as Orally Bioavailable Blood–Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer’s Disease: Discovery of SB-1448

Abstract

The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of <i>Embelia ribes</i> Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin-aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, <b>9j</b> (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC₅₀ values of 0.15, 1.6, and 0.6 μM, respectively. It inhibits both ChEs noncompetitively with <i>k</i>_i values of 0.21 and 1.3 μM, respectively. It is orally bioavailable, crosses blood-brain barrier (BBB), inhibits Aβ self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of <b>9j</b> at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.