LAUSR

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 IC50 values of 0.5, 4.3, and 11.9 μM, respectively and excellent BBB permeability (Pe = 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 IC50 values of 0.44, 3.8, and 17.9 μM, respectively. The ether analog also inhibits self‐aggregation of Aβ and crosses BBB (Pe = 7.3 × 10−6 cm/s). Administration of 13 at 5 mg/kg (iv) in Wistar rats showed excellent plasma exposure with AUC0−∞ of 28,834 ng min/ml. In conclusion, the multitargeted berberrubine ether derivative 13 is CNS permeable and has good ADME properties.