Arylbenzofurans from the Root Bark of Morus alba as Triple Inhibitors of Cholinesterase, β-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3β: Relevance to Alzheimer’s Disease

Abstract

Cholinesterase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and glycogen synthase kinase-3β (GSK-3β) are the three main enzymes responsible for the early onset of Alzheimer’s disease (AD). The main aim of the present study was to delineate and accentuate the triple-inhibitory potential of arylbenzofurans from Morus alba against these enzymes. Overall, the enzyme inhibition assays demonstrated the prominence of mulberrofuran D2 as an inhibitor of AChE, BChE, BACE1, and GSK-3β enzymes with IC 50 values of 4.61, 1.51, 0.73, and 6.36 μM, respectively. Enzyme kinetics revealed different modes of inhibition, and in silico modeling suggested that mulberrofuran D2 inhibited these enzymes with low binding energy through hydrophilic, hydrophobic, and π–cation interactions in the active site cavities. Similarly, in Aβ-aggregation assays, mulberrofuran D2 inhibited self-induced and AChE-induced Aβ aggregation in a concentration-dependent manner that was superior to reference drugs. These results suggest that arylbenzofurans from M. alba , especially mulberrofuran D2, are triple inhibitors of cholinesterase, BACE1, and GSK-3β and may represent a novel class of anti-AD drugs.

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity

“…These two compounds have been used as references in many studies on AChE and BACE-1 inhibition. The results showed that the biological activities of the positive controls in this study are comparative to previously published values [ 34 , 35 , 36 ].…”

Synthesis, In Silico and In Vitro Evaluation for Acetylcholinesterase and BACE-1 Inhibitory Activity of Some N-Substituted-4-Phenothiazine-Chalcones

“…These two compounds have been used as references in many studies on AChE and BACE-1 inhibition. The results show that the biological activities of the positive controls in this study are comparative to the previously published values [ 56 , 57 , 58 ]. On the other hand, the experimental assays also specified that AC12 had a higher activity than galantamine on AChE and all the synthesized chalcones exhibited the higher inhibiting effects than quercetin on BACE-1.…”

Anti-Alzheimer’s Disease Activity of Bromophenols from a Red Alga, Symphyocladia latiuscula (Harvey) Yamada

“…Bromophenols 1 – 3 were accessed for their ability to inhibit self-induced Aβ 25–35 aggregations via the thioflavin T (ThT) fluorescence method, 53 with slight modifications. 54 In brief, Aβ 25–35 , lyophilized from 1mg/mL hexafluoro-2-propanol (HFIP) solution, was dissolved in 65% acetonitrile to obtain 0.4 mM stock solution. Then the stock solution of Aβ 25–35 was diluted by 2-fold in 69 mM phosphate buffer (pH 7.0).…”