Explore the vast range of titles available.

Alzheimer’s disease (AD) involves a complex pathophysiology with multiple interconnected subpathologies, including protein aggregation, impaired neurotransmission, oxidative stress, and microglia-mediated neuroinflammation. Current treatments, which generally target a single subpathology, have failed to modify the disease’s progression, providing only temporary symptom relief. Multi-target drugs (MTDs) address several subpathologies, including impaired aggregation of pathological proteins. In this review, we cover hybrid molecules published between 2014 and 2024. We offer an overview of the strategies employed in drug design and approaches that have led to notable improvements and reduced hepatotoxicity. Our aim is to offer insights into the potential development of new Alzheimer’s disease drugs. This overview highlights the potential of multi-target drugs featuring heterocycles with N-benzylpiperidine fragments and natural compounds in improving Alzheimer’s disease treatment.

Among neurodegenerative disorders, Alzheimer's disease (AD) is one of the most common disorders showing slow progressive cognitive decline. Targeting acetylcholinesterase (AChE) is one of the major strategies for AD therapeutics, as cholinergic pathways in the cerebral cortex and basal forebrain are compromised. Herein, we report the design of some copper and other metal based donepezil derivatives, employing density functional theory (DFT). All designed compounds are optimized at the B3LYP/SDD level of theory. Dipole moments, electronic energie, enthalpies, Gibbs free energies, and HOMO-LUMO gaps of these modified compounds are also investigated in the subsequent analysis. The molecules were then subjected to molecular docking analysis with AChE to study the molecular interactions broadly. Ensemble based docking and molecular dynamics (MD) simulations of the best candidates were also performed. Docking and MD simulation reveal that modified drugs are more potent than unmodified donepezil, where Trp86, Tyr337, Phe330 residues play some important roles in drug-receptor interactions. According to ensemble based docking, D9 shows greater binding affinity compared to the parent in most conformations obtained from protein data bank and MD simulation. In addition, it is observed that the π- π stacking with the residues of Trp86, Tyr337, Tyr341, Tyr124 and Trp286 may be required for strong ligand binding. Moreover, ADME/T analysis suggests that modified derivatives are less toxic and have improved pharmacokinetic properties than those of the parent drug. These results further confirm the ability of metal-directed drugs to bind simultaneously to the active sites of AChE and support them as potential candidates for the future treatment of Alzheimer's disease.

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.

Alzheimer’s disease (AD) is a significant concern in the elderly, characterized by impaired cholinergic transmission,decreased choline acetyltransferase activity and increased acetylcholinesterase (AChE) activity, resulting in reduced acetylcholine levels. First‐generation AChE inhibitors (AChEIs), including tacrine, and second‐generation agents, such as donepezil, galantamine, and rivastigmine, offer only limited symptomatic relief. More comprehensive drug treatment plans are in demand. AChE, crucial for acetylcholine regulation, is a key focus due to its altered activity in AD. Enhancing cholinergic activity via AChEIs remains a viable strategy, exemplified by Donepezil. However, the effectiveness of Donepezil as an AD therapeutic is limited by various side effects and solubility issues. In this study, we used a structure‐guided strategy to screen Donepezil analogs for the identification of potential compounds for AChE inhibition. We identified two Donepezil‐like compounds (PubChem CIDs 14553578 and 19820656) that show a higher predicted binding affinity and stability with AChE in our in silico workflow compared with Donepezil. These findings are computational and hypothesis‐generating; experimental biochemical and pharmacological validation, such as in vitro enzymatic IC 50 determinations, cellular ADME/Tox profiling, and in vivo studies, will be required to confirm biological activity and therapeutic potential.

A simple and mild strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes that acts via a radical-mediated mechanism and uses commercial photocatalysts. Light-induced trifluoromethylation of potential drugs Premature metabolic decomposition can stop potentially promising drugs from reaching their intended targets. One way of blocking this metabolism involves the addition of a trifluoromethyl (CF 3 ) group to aromatic or heteroaromatic moieties in a candidate drug molecule. David Nagib and David MacMillan report a new method for this synthesis that is more economical than current methods in terms of both raw materials and energy input. They use an energy-saving compact fluorescent light bulb to excite a variety of commercially available photocatalysts, which promote the addition of CF 3 to unactivated arenes and heteroarenes through a radical-mediated mechanism. The potential of the method is demonstrated by the trifluoromethylation of three molecules: a uracil analogue, a precursor of the acetylcholinesterase inhibitor donepezil and a vitamin (flavone). Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents 1 . One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion 2 . A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF 3 ) group, into drug candidates 3 . The CF 3 group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug 4 , 5 , 6 . Although common pharmacophores often bear CF 3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF 3 group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF 3 to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.

PurposePharmacological modulation of parasympathetic activity with donepezil, an acetylcholinesterase inhibitor, improves the long-term survival of rats with chronic heart failure (CHF) after myocardial infarction (MI). However, its mechanism is not well understood. The α7-nicotinic acetylcholine receptor (α7-nAChR) reportedly plays an important role in the cholinergic anti-inflammatory pathway. The purpose of this study was to examine whether blockade of α7-nAChR, either centrally or peripherally, affects cardioprotection by donepezil during CHF.MethodsOne-week post-MI, the surviving rats were implanted with an electrocardiogram or blood pressure transmitter to monitor hemodynamics continuously. Seven days after implantation, the MI rats (n = 74) were administered donepezil in drinking water or were untreated (UT). Donepezil-treated MI rats were randomly assigned to the following four groups: peripheral infusion of saline (SPDT) or an α7-nAChR antagonist methyllycaconitine (α7PDT), and brain infusion of saline (SBDT) or the α7-nAChR antagonist (α7BDT).ResultsAfter the 4-week treatment, the role of α7-nAChR was evaluated using hemodynamic parameters, neurohumoral states, and histological and morphological assessment. Between the peripheral infusion groups, α7PDT (vs. SPDT) showed significantly increased heart weight and cardiac fibrosis, deteriorated hemodynamics, increased plasma neurohumoral and cytokine levels, and significantly decreased microvessel density (as assessed by anti-von Willebrand factor–positive cells). In contrast, between the brain infusion groups, α7BDT (vs. SBDT) showed no changes in either cardiac remodeling or hemodynamics.ConclusionPeripheral blockade of α7-nAChR significantly attenuated the cardioprotective effects of donepezil in CHF rats, whereas central blockade did not. This suggests that peripheral activation of α7-nAChR plays an important role in cholinergic pharmacotherapy for CHF.

Alzheimer's disease (AD) is the most common cause of dementia in older adults and is becoming a major public health crisis as life expectancy increases worldwide. A major contributor to this disease is a deficiency in melatonin signaling. We have recently synthesised a series of melatonin analogs containing donepezil fragments. These compounds have been tested both in silico and in vitro. In this study, a particularly potent compound, , was evaluated in a hybrid rat model of melatonin deficiency and AD. Rats underwent pinealectomy followed one week later by bilateral intracerebroventricular infusion of Aβ (1 µg/µL). A 14-day subchronic treatment with compound was started simultaneously with the neurotoxin infusion. Melatonin was used as a reference drug, while a matched sham group received vehicle treatment. One week after the Aβ infusion, the rats' cognitive functions were assessed using two Y-maze protocols, object recognition and object location tests. Markers of oxidative stress, including hippocampal glutathione, superoxide dismutase, and malondialdehyde, were assessed by ELISA. Compound effectively prevented cognitive impairment induced by the AD model, and its effects were comparable to those of melatonin. In addition, this melatonin analogue with a donepezil fragment reduced AD-associated oxidative stress and suppressed model-associated increased Aβ levels in the hippocampus. Our findings suggest that melatonin analogs containing donepezil fragments are promising therapeutic options for targeting oxidative stress associated with AD.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, poses a significant global health burden due to its intricate pathology and the absence of curative treatments. Current therapies primarily offer symptomatic relief, often with limited efficacy and complications, thereby underscoring the urgent need for innovative, safer, and more effective interventions. Stigmasterol, a plant-derived phytosterol, has demonstrated neuroprotective properties, including anti-inflammatory and antioxidant effects, which positions this sterol as a compelling candidate for further investigation in AD treatment. In this investigation, high-throughput virtual screening of 972 stigmasterol analogs (SAs) was conducted to identify potential acetylcholinesterase (AChE) inhibitors, followed by ADMET filtering, molecular dynamics (MD) simulations, MM/GBSA free binding energy estimations, and DFT calculations. Three lead compounds, including SA4 (-10.9 kcal/mol), SA12 (-10.6 kcal/mol), and SA15 (-10.5 kcal/mol), demonstrated superior binding affinities compared to stigmasterol (-9.6 kcal/mol) and the control drug donepezil (-8.6 kcal/mol). Docking interaction analysis revealed strong binding by hydrogen bonds and hydrophobic interactions, whereas pharmacokinetic, pharmacodynamic, and toxicity assessments confirmed the favorable characteristics of these compounds. MD simulations (200 ns) demonstrated the structural compactness of the compounds, which was further supported by principal component analysis and Gibbs free energy landscape experiments. MM/GBSA identified SA4 as the most potent analog (-82.21 kcal/mol), followed by SA15 (-80.40 kcal/mol) and SA12 (-69.72 kcal/mol). A DFT-based molecular reactivity analysis revealed decreased reactivity and increased kinetic stability of the lead candidates in their transition from free to bound states. These findings provide insights into the therapeutic potential of stigmasterol analogs as AChE inhibitors, thus offering the groundwork for in vivo and in vitro validation for advancing AD treatment.

Alzheimers disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) which is the most common cause of dementia in the elderly. It is characterized by the deficits in the cholinergic system and presence of characteristic hallmarks: neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes it became a target for the design of antialzheimer drugs. Cholinesterase inhibitors enhance cholinergic transmission indirectly, by inhibiting the enzyme which hydrolyses acetylcholine. It has been also demonstrated that acetylcholinesterase (AChE) is involved in the developement of amyloid plaques. Therefore, substances which are AChE inhibitors (AChEI) are the only drugs approved for the symptomatic treatment of AD. This review presents the main classes of cholinesterase inhibitors developed recently for the treatment of AD. We have started with the analogues of the existing drugs: tacrine, donepezil, rivastigmine and galantamine which are still of interest for many research groups. Among them there is a very interesting group - dual binding site inhibitors characterized by increased inhibitory potency against AChE and amyloid plaques formation. There is also a group of compounds with additional properties such as: antioxidant activity, affinity to 5-HT3 receptors, inhibition of N-methyltransferase that metabolize histamine, which can be beneficial for the treatment of AD. Furthermore there are some interesting compounds which belong to different chemical groups also of natural origin. In this review we sum up current research concerned with development of AChEIs which can be more effective in the future treatment of AD.

Background and purpose Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha‐synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending phenoconversion. Methods Twenty‐one polysomnography‐confirmed iRBD patients underwent baseline 11C‐donepezil and 6‐Fluoro‐(18F)‐l‐3,4‐dihydroxyphenylalanine (18F‐DOPA) positron emission tomography (PET). Potential phenoconversion was monitored for up to 8 years. PET images were analysed according to patients' diagnoses after 3 and 8 years using linear regression. Time‐to‐event analysis was made with Cox regression, dividing patients into low and high tracer uptake groups. Results Follow‐up was accomplished in 17 patients. Eight patients progressed to either Parkinson's disease (n = 4) or dementia with Lewy bodies (n = 4), while nine remained non‐phenoconverters. Compared with non‐phenoconverters, 8‐year phenoconverters had lower mean 11C‐donepezil uptake in the parietal (p = 0.032) and frontal cortex (p = 0.042), whereas mean 11C‐donepezil uptake in 3‐year phenoconverters was lower in the parietal cortex (p = 0.005), frontal cortex (p = 0.025), thalamus (p = 0.043) and putamen (p = 0.049). Phenoconverters within 3 years and 8 years had lower 18F‐DOPA uptake in the putamen (p < 0.001). iRBD patients with low parietal 11C‐donepezil uptake had a 13.46 (95% confidence interval 1.42;127.21) times higher rate of phenoconversion compared with those with higher uptake (p = 0.023). iRBD patients with low 18F‐DOPA uptake in the most affected putamen were all phenoconverters with higher rate of phenoconversion (p = 0.0002). Conclusions These findings suggest that cortical cholinergic dysfunction, particularly within the parietal cortex, could be a biomarker candidate for predicting short‐term phenoconversion in iRBD patients. This study aligns with previous reports suggesting dopaminergic dysfunction is associated with forthcoming phenoconversion.