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 Embelia ribes 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, 9j (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 k 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 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.

Synthesis of novel rapanone derivatives via organocatalytic reductive C-alkylation: biological evaluation of antioxidant properties, in vivo zebrafish embryo toxicity, and docking studies

“…The fractions were 31-71 (R f 0.42), matched with standard rapanone (R f 0.42) in TLC, which was observed in white light, mobile phase (chloroform 50%, ethyl acetate 45%, and formic acid 5%). 9,35 This similar rapanone fraction was evaporated in the rotary evaporator until a constant weight of 20.11 g was obtained (44.60% yield). The finally isolated (1) was confirmed by 1 H, 13 C NMR, and (ESI †) HRMS spectra.…”

“…Rapanone is a naturally occurring benzoquinone isolated from the medicinal plant Embelia ribes ( Myrsinaceae ). 1 This compound exhibits a broad spectrum of biological activities, 2 including antioxidant, 3 anti-inflammatory, 4 anticonvulsant, 5 anxiolytic, 6 antitumor, 7 antibacterial, 8 vulsant, 9 and antifertility 10 properties. More than 50 natural products are derivatives of bioactive compounds ( A , B , C , D , and E ), which share the backbone of rapanone 11 (Fig.…”

Identification of Azelastine and Carvedilol as Cholinesterase Inhibitors via Structure‐Based Virtual Screening of FDA‐approved Drugs

“…[5] Acetylcholinesterase (AChE) is one of the major enzymes involved in the regulation of acetylcholine at the synaptic cleft of neurons, confirming the proper functioning of neurotransmission. [6] AChE cleaves acetylcholine into choline and acetate ions; thus, decreasing its levels in the synaptic cleft. [7] The crystal structure of AChE revealed that the shape of the enzymatic cavity has a 20 Å deep narrow gorge in its center.…”

Novel Lawsone–Quinoxaline Hybrids as New Dual Binding Site Acetylcholinesterase Inhibitors

“…Recent studies have also shed light on the neuroprotective effects, acetylcholinesterase inhibition, and Aβ aggregation inhibition performed by 1,4-NQ-derived compounds. − Lawsone (2-hydroxy-1,4-napthoquinone) is the main natural dye from the leaves of Henna plants . AChEI activity of some synthetic lawsone derivatives and lawsone-like derivatives was reported. − According to the in silico simulations, the 1,4-NQ system interacted with amino acid residues along the AChE active site gorge. , The para-quinone moiety primarily interacted with the amino acid residues at the CAS site, while the aromatic ring interacted with the amino acid residues in the PAS. , Therefore, lawsone was proposed to be a CAS ligand for the design of the hybrid molecule that act as dual binding site AChE inhibitors.…”