Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities

Abstract

The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63–4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen–glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, 6bd could cross the blood–brain barrier in vitro. More importantly, compared to edaravone, 6bd had stronger free-radical scavenging activity. Molecular docking studies revealed that 6bd could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate 6bd as a leading structure worthy of further investigation.

CZK, a novel alkaloid derivative from Clausena lansium, alleviates ischemic stroke injury through Nrf2-mediated antioxidant effects

“…Previous studies revealed that Clausena lansium had an excellent therapeutic effect in the therapy of Parkinson's disease and Alzheimer's disease 16,30 . Claulansine F, a carbazole alkaloid isolated from Clausena lansium, had a strong neuroprotective activity that could promote neurogenesis, neuronal differentiation, anti-apoptosis, and free radicals scavenging [31][32][33][34] . However, toxicity is an integral part of its drug development.…”

Phyto-Carbazole Alkaloids from the Rutaceae Family as Potential Protective Agents against Neurodegenerative Diseases

“…The Clau F-donepezil hybrids exhibited potent AChE inhibition (IC 50 6bd) demonstrated superior neuroprotective effects in comparison to Clau F against OGD/reoxygenation (OGD/R). Additionally, the compound 6bd displayed good BBB penetration (Permeability: Pe × 10 −6 cm•s −1 ) in parallel artificial membrane permeation assay (PAMPA) [25].…”

“…Among the naturally occurring phyto-carbazole alkaloids, mahanimbine, koenimbine, koenigicine and clausazoline-K were reported to possess anti-lipase activity [14,15], while mahanine, pyrayafoline-D and murrafoline-I displayed anticancer activities by inducing apoptosis through activating the caspase-9/caspase-3 pathway [16]. Both natural and synthetic derivatives of carbazole alkaloids have revealed numerous pharmacological activities, such as anticancer [17], antioxidant [18], anti-inflammatory [19], antibacterial [20], antifungal [21], antidiabetic [22], antiangiogenic [23], larvicidal [24], antiplant virus [25], anti-HIV [26], and neuroprotective activities [13]. In particular, carbazolecontaining arylcarboxamides and carbazole thiazoles are inhibitors of β-secretase (BACE-1: the enzyme responsible for the production of β-amyloid (Aβ)) and Aβ formation, respectively [27,28].…”