donepezil (IPI301 / donepezil, iCure / Donerion)

Rational design and synthesis of dispiroindene-pyrrolidinedione scaffolds as multi-target directed ligands: potent AChE inhibitors with antioxidant activity and favorable biocompatibility in SH-SY5Y cells.

Morsy Nagy A NA, El-Shiekh Riham A RA, Ebrahium Mohamad M MM, Srour Aladdin M AM

Addressing the urgent need for multi-target therapies in Alzheimer's disease, we report the rational design and one-pot, multi-component synthesis of novel substituted dispiroindene-pyrrolidinedione scaffolds (4a-r). Systematic biological evaluation identified five lead compounds (4g, 4j, 4k, 4m, and 4p) with potent inhibitory activity. Derivative 4k emerged as the primary lead, exhibiting an IC50 for Acetylcholinesterase (AChE) of 2.58 ± 0.11 μM and a remarkable selectivity index of 15.71, significantly exceeding that of donepezil (4.37), the reference drug. Concurrently, the series demonstrated notable affinity for Butyrylcholinesterase (BChE), with several derivatives exhibiting submicromolar to low micromolar inhibition. Furthermore, these scaffolds demonstrated superior antioxidant potential; notably, compound 4p achieved an IC50 value of 25.23 ± 1.25 μM, demonstrating an approximate 5-fold increase in radical scavenging potency relative to ascorbic acid (128.20 μM). In vitro safety assays on SH-SY5Y human neuroblastoma cells confirmed excellent biocompatibility, with compound 4m displaying an IC50 of 125.00 ± 6.91 μM, nearly four times less toxic than donepezil (32.84 μM). Molecular docking validated these results, showing robust π-π stacking and halogen-based stabilization within the catalytic anionic site. These findings, supported by ADME profiles predicting high blood-brain barrier permeability, position the dispiroindene-pyrrolidinedione framework as a highly effective, low-toxicity, multi-functional candidate for the development of Alzheimer's disease therapeutics.

Donepezil-induced manic episodes in two patients with different types of dementia.

Yilmaz Melek Kandemir MK

Diindolylmethane confers nootropic and neuroprotection effects against scopolamine-induced brain injury in Wistar rats.

Anusha Vinjavarapu Lakshmi VL, Dontiboina Hari Krishna Reddy HKR, Yadava Srikanth S, Dumala Naresh N et al.

This study investigated the 3,3'-Diindolylmethane (DIM) memory-enhancing and neuroprotective effects in Wistar rats against scopolamine (Scop)-induced neurotoxicity. Rats were divided into six groups: healthy control, Scop (1 mg/kg), DIM (25, 50, and 100 mg/kg), and donepezil (5 mg/kg). All groups except the control received Scop for 14 days, with DIM or DPZ administered concurrently. NORT and Y-maze tests were employed to assess cognition and memory. Activity of acetylcholinesterase (AChE), acetylcholine (ACh) levels, oxidative stress parameters (MDA, ROS, SOD, CAT, NRF2, HO-1), inflammatory mediators (TNF-α, NF-κB, IL-6, IL-10), and apoptotic factors (cytochrome c, and caspases) were measured in brain samples, and H&E staining was performed. DIM significantly improved cognition and memory as demonstrated by enhanced spontaneous alternations (%) and recognition index from behavioural analysis. DIM reduces AChE activity and increases ACh levels, indicating that improvement in cholinergic function is the reason for improved cognition and memory. Additionally, DIM treatment enhanced the antioxidant markers like CAT, SOD, NRF2, and HO-1, while reducing the total ROS and MDA levels in the brain, indicating its antioxidant potential. Similarly, DIM attenuated neuroinflammatory mediators IL-6, TNF-α, NF-κB, and elevated IL-10, an anti-inflammatory cytokine, suggesting DIM acts as an anti-inflammatory agent. Moreover, DIM reduced the neuronal apoptosis markers, cytochrome C, caspase 9 and 3, and improved the hippocampal CA1 neuronal architecture, indicating that it preserved the neuronal architecture. Correlation analysis between memory and other biochemical parameters provides a stronger negative correlation with AchE and neuroinflammation and a positive correlation with NRF2, indicating that DIM enhanced memory and neuroprotection involved multiple pathways. In conclusion, DIM enhances cognition and memory by improving cholinergic dysfunction and exhibits neuroprotective effects by reducing oxidative stress, inflammation, and apoptosis against scopolamine-induced neurotoxicity.

Design and synthesis of new donepezil-based chalcones as multi-target-directed ligands against Alzheimer's disease: biological evaluation, molecular dynamics, and zebrafish model studies.

Geraiely Babak B, Kianmehr Ebrahim E, Iraji Aida A, Bukhari Syed Nasir Abbas SNA et al.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by several hallmarks, including cholinergic dysfunction, aggregation of amyloid beta (Aβ), oxidative stress, and metal ion dyshomeostasis. A series of donepezil-derived chalcones 7a-q were synthesized and tested for their ability to inhibit cholinesterase (ChE) and amyloid beta (Aβ) aggregation, antioxidant properties, and metal chelation. Of these, compound 7j with a 2-chloroaryl moiety showed moderate anti-AChE activity (IC50 = 17.96 µM) and showed potent inhibition of Aβ aggregation, both in the presence of self-induced (72.5%) and AChE-induced (77.6%) conditions, and had good Cu2+ chelation ability, which was confirmed by ultraviolet-visible (UV-vis) spectroscopy. Compound 7p, an analog containing furan, exhibited both anti-ChE activity (IC50 = 22.70 µM for AChE and 19.14 µM for BuChE, respectively) and moderate anti-Aβ aggregation activity, as well as moderate antioxidant activity. The two compounds were found to be safe, also in PC12 cells and SH-SY5Y cells. Their results are all encouraging for their use as multi-target directed ligands (MTDLs) against AD. Finally, the molecular dynamics simulations in the active site of AChE of compound 7j showed stable binding for 100 nanoseconds. In vivo experiments in zebrafish showed that compound 7p markedly enhanced locomotor and exploratory behavior, with a therapeutic profile compared to the standard drug donepezil, and compound 7j exhibited moderate therapeutic effects.