Multitargeted C9‐substituted ester and ether derivatives of berberrubine for Alzheimer's disease: Design, synthesis, biological evaluation, metabolic stability, and pharmacokinetics

Abstract

Berberrubine is a naturally occurring isoquinoline alkaloid and a bioactive metabolite of berberine. Berberine exhibits a wide range of pharmacological activities, including cholinesterase inhibition. The cholinesterase inhibitors provide symptomatic treatment for Alzheimer's disease; however, multitarget-directed ligands have the potential as disease-modifying therapeutics. Herein, we prepared a series of C9-substituted berberrubine derivatives intending to discover dual cholinesterase and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Most synthesized derivatives possessed balanced dual inhibition (AChE and BChE) activity in the submicromolar range and a moderate inhibition against BACE-1. Two most active ester derivatives, 12a and 11d, display inhibition of AChE, BChE, and BACE-1. The 3-methoxybenzoyl ester derivative, 12a, inhibits electric eel acetylcholinesterase (EeAChE), equine serum butyrylcholinesterase (eqBChE), and human hBACE-1 with IC 50 values of 0.5, 4.3, and 11.9 μM, respectively and excellent BBB permeability (P e = 8 × 10 −6 cm/s). The ester derivative 12a is metabolically unstable; however, its ether analog 13 is stable in HLM and exhibits inhibition of AChE, BChE, and BACE-1 with IC 50 values of 0.44, 3.8, and 17.9 μM, respectively. The ether analog also inhibits self-aggregation of Aβ and crosses BBB (P e = 7.3 × 10 −6 cm/s). Administration of 13 at 5 mg/kg (iv) in Wistar rats showed excellent plasma exposure with AUC 0−∞ of 28,834 ng min/ml.In conclusion, the multitargeted berberrubine ether derivative 13 is CNS permeable and has good ADME properties.

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

“…There is an incredible contribution of natural products (NPs) to drug discovery in general and particularly in the CNS domain (84% of the marketed drugs in the CNS domain are either pure NPs or NP-inspired molecules). − In continuation to our continuous efforts on exploring natural products for CNS diseases, − herein, the hydroxybenzoquinone natural product, embelin ( 1 ), was pursued for medicinal chemistry lead optimization in search of optimized MTDL for AD. Embelin ( 1 ) is an MTDL showing inhibition of AChE, BChE, and BACE-1 with respective IC 50 values of 2.5, 5.45, and 2.11 μM and also has an ability to bind Aβ and prevent its accumulation. , The ameliorating potential of embelin against scopolamine-induced amnesia and streptozotocin-induced cognitive impairment was proved in rat models.…”

Synthesis and Biological Evaluation of Coumarin Triazoles as Dual Inhibitors of Cholinesterases and β-Secretase

“…Donepezil is an FDA-approved ChE inhibitor. The commercially available β-Secretase inhibitor IV was used as a positive control for BACE-1 . The 4-hydroxycoumarin 5 is a poor inhibitor of AChE, BChE, and BACE-1.…”

“…The commercially available β-Secretase inhibitor IV was used as a positive control for BACE-1. 25 The 4-hydroxycoumarin 5 is a poor inhibitor of AChE, BChE, and BACE-1. The condensation of 5 with the benzyl triazole did not significantly boost the inhibition of ChEs; however, a marginal improvement in BACE-1 inhibition was observed ( 5 vs 8a ).…”

Function of proprotein convertase subtilisin/kexin type 9 and its role in central nervous system diseases: An update on clinical evidence

“…However, other RCTs and real world study reveled that PCSK9 inhibitor therapy had higher rates of neurocognitive adverse events (di Mauro et al, 2021; Gouverneur et al, 2023; Lipinski et al, 2016; Robinson et al, 2015). AD, an irreversible neurodegenerative disease involving the degradation of memory and other cognitive functions (Raghuvanshi et al, 2023), has also achieved mixed results. In clinical trials, cerebrospinal fluid PCSK9 levels were positively correlated with the AD risk, especially in female (Courtemanche et al, 2018; Picard et al, 2019).…”