Multifunctional Anti-Alzheimer Research Articles

Quercetin-1,2,3-Triazole Hybrids as Multifunctional Anti-Alzheimer's Agents.

The number of patients with Alzheimer's disease (AD) continues to rise and, despite the efforts of researchers, there are still no effective treatments for this multifaceted disease. The main objective of this work was the search for multifunctional and more effective anti-Alzheimer agents. Herein, we report the evaluation of a library of quercetin-1,2,3-triazole hybrids (I-IV) in antioxidant, hydrogen peroxide-induced oxidative stress protection, and cholinesterases (AChE and BuChE) inhibitory activities. Hybrids IIf and IVa-d showed potent in vitro inhibitory activity on eqBuChE (IC50 values between 11.2 and 65.7 μM). Hybrid IIf, the best inhibitor, was stronger than galantamine, displaying an IC50 value of 11.2 μM for eqBuChE, and is also a competitive inhibitor. Moreover, toxicity evaluation for the most promising hybrids was performed using the Artemia salina toxicity assay, showing low toxicity. Hybrids IIf, IVb, and IVd did not affect viability at 12.5 μM and also displayed a protective effect against oxidative stress induced by hydrogen peroxide in cell damage in MCF-7 cells. Hybrids IIf, IVb, and IVd act as multifunctional ligands in AD pathologies.

Anti-Alzheimer potential of coumarin derivatives: A review

Alzheimer’s is a type of neurodegenerative diseases (NDs) found in old age people which main causes the dementia and various brain disorders. FDA approved drugs used commonly in treatment of moderate to severe Alzheimer's disease are Donepezil, Rivastigmine, Galantamine and Memantine. However, these approved drugs provide only palliative support not complete cure. So, urgency of new molecules has been becoming so important to cure this complex Disease. Coumarin or 2-H-Chromen-2-one is an oxygenated heterocyclic compound, which is isolated from plants named Dipteryx odorata Willd, (Fabaceae). Synthetic coumarin derivatives has been well presence in literature due to existence of their potential pharmacological activities in literature. This review covers the anti-Alzheimer activities of chemically synthesized coumarin derivatives from 2016-2023. Coumarin derivatives profound found exhibits potential anti-Alzheimer activities in literature. Coumarin derivatives showed their anti-Alzheimer potential through various pharmacological pathways such as monoamine oxidase (MAO) inhibitor, acetylcholinesterase (AChE) & Butyl cholinesterase (BuChE) inhibitory activity, Aβ amyloid inhibition, Beta secretase 1 (BACE1 inhibitors). Multi-target directed ligands (MTDLs) approach also extensively reported to design and synthesis of novel coumarin scaffold as potential multifunctional Anti-Alzheimer activities in last one decade. We also covered literature of some coumarin hybrids derivatives as potential Anti-Alzheimer activities. Some common synthetic methods of coumarin structure also covered in this review article. This review supported that coumarin derivatives found excellent anti-Alzheimer activities and it can be play major role to solve the problem of complex AD disease.

Design, Synthesis, and In Vitro and In Silico Approaches of Novel Indanone Derivatives as Multifunctional Anti-Alzheimer Agents.

Alzheimer's disease (AD) is a neurological, progressive illness that typically affects the elderly and is clinically distinguished by memory and cognitive decline. Due to a number of factors, including the absence of a radical treatment, an increase in the patient population over time, the high cost of care and treatment, and a significant decline in patients' quality of life, the importance of this disease has increased. These factors have all prompted increased interest among researchers in this field. The chemical structure of the donepezil molecule, the most popular and effective treatment response for AD, served as the basis for the design and synthesis of 42 novel indan-1-one derivatives in this study. Using IR, 1H, and 13C NMR as well as mass spectroscopic techniques, the compounds' structures were identified. Research on the compounds' antioxidant activities, cholinesterase (ChE) enzyme inhibition, monoamine oxidase (MAO) A and B inhibitory activities, β-amyloid plaque inhibition, and cytotoxicity impact was carried out. Inhibition of β-amyloid plaque aggregation; effective inhibition of AChE, BChE, and MAO-B enzymes; and significant antioxidant activity were all demonstrated by compounds D28-D30 and D37-D39. Because of their various actions, it was hypothesized that the related compounds may be useful in treating AD symptoms as well as providing palliative care.

Novel Donepezil-Chalcone-Rivastigmine Hybrids as Potential Multifunctional Anti-Alzheimer's Agents: Design, Synthesis, in Vitro Bilogical Evaluation, in Silico Study, Molecular Dynamics Simulation, Druggability, PET-CT Imaging Analysis and in Vivo Study

Novel Donepezil-Chalcone-Rivastigmine Hybrids as Potential Multifunctional Anti-Alzheimer's Agents: Design, Synthesis, in Vitro Bilogical Evaluation, in Silico Study, Molecular Dynamics Simulation, Druggability, PET-CT Imaging Analysis and in Vivo Study

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

In Alzheimer’s disease, neurons slowly degenerate due to the accumulation of misfolded amyloid β and tau proteins. In our research, we performed extended studies directed at amyloid β and tau aggregation inhibition using in cellulo (Escherichia coli model of protein aggregation), in silico, and in vitro kinetic studies. We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional anti-Alzheimer’s agents and identified very potent dual aggregation inhibitors. Among the tested derivatives, we selected compound 18, which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aβ42 inhibition (inh.) 80.0%, tau inh. 68.3% in 10 μM), with previously reported in vitro inhibitory activity against hBuChE, hBACE1, and Aβ (hBuChE IC50 = 5.74 μM; hBACE1 IC50 = 41.6 μM; Aβ aggregation (aggr.) inh. IC50 = 3.09 μM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aβ vs tau. Moreover, docking and kinetic studies showed that compound 18 could inhibit the amyloid aggregation process at several steps and also displayed disaggregating properties. These results may help to design the next generations of dual or selective aggregation inhibitors.

Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-Hydroxyalkyl)Isoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents.

The complex nature of Alzheimer’s disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkyl)isoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward β-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE), equine serum butyrylcholinesterase (eqBuChE), human β-secretase (hBACE-1), and β-amyloid (Aβ-aggregation). The most promising compound, 12 (2-(5-(benzylamino)-4-hydroxypentyl)isoindoline-1,3-dione), displayed inhibitory potency against eeAChE (IC50 = 3.33 μM), hBACE-1 (43.7% at 50 μM), and Aβ-aggregation (24.9% at 10 μM). Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes—acetylcholinesterase and β-secretase. In conclusion: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer’s agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: β-secretase and Aβ-aggregation.

Design, Synthesis, and Biological Evaluation of 1-Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer's Agents.

The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of β-secretase (IC50 hBACE-1 = 41.60 μM), inhibition of amyloid β aggregation (IC50Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.

Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent.

In our study, we attempted to investigate the influences of P-glycoprotein (P-gp) on DL0410, a novel synthetic molecule for Alzheimer’s disease (AD) treatment, for intestinal absorption and blood-brain barrier permeability in vitro and related binding mechanisms in silico. Caco-2, MDCK, and MDCK-MDR1 cells were utilized for transport studies, and homology modelling of human P-gp was built for further docking study to uncover the binding mode of DL0410. The results showed that the apparent permeability (Papp) value of DL0410 was approximately 1 × 10−6 cm/s, indicating the low permeability of DL0410. With the presence of verapamil, the directional transport of DL0410 disappeared in Caco-2 and MDCK-MDR1 cells, suggesting that DL0410 should be a substrate of P-gp, which was also confirmed by P-gp ATPase assay. In addition, DL0410 could competitively inhibit the transport of Rho123, a P-gp known substrate. According to molecular docking, we also found that DL0410 could bind to the drug binding pocket (DBP), but not the nucleotide binding domain (NBD). In conclusion, DL0410 was a substrate as well as a competitive inhibitor of P-gp, and P-gp had a remarkable impact on the intestine and brain permeability of DL0410, which is of significance for drug research and development.

Design, Synthesis and Evaluation of Hesperetin Derivatives as Potential Multifunctional Anti-Alzheimer Agents.

In this study we designed and synthesized a series of new hesperetin derivatives on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of the novel derivatives was also evaluated. Results showed that the synthesized hesperetin derivatives displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (selectivity index values from 68 to 305). The Lineweaver-Burk plot and molecular docking study showed that these compounds targeted both the peripheral anionic site (PAS) and catalytic active site (CAS) of AChE. The derivatives also showed a potent self-induced β-amyloid (Aβ) aggregation inhibition and a peroxyl radical absorbance activity. Moreover, compound 4f significantly protected PC12 neurons against H2O2-induced cell death at low concentrations. Cytotoxicity assay showed that the low concentration of the derivatives does not affect the viability of the SH-SY5Y neurons. Thus, these hesperetin derivatives are potential multifunctional agents for further development for the treatment of Alzheimer’s disease.

Synthesis, Docking and Evaluation of Novel Pyrazole Carboxamide Derivatives as Multifunctional Anti-Alzheimer's Agents

Synthesis, Docking and Evaluation of Novel Pyrazole Carboxamide Derivatives as Multifunctional Anti-Alzheimer's Agents

Design, Synthesis and Evaluation of Genistein-polyamine Conjugates as Multi-functional Anti-Alzheimer Agents

Design, Synthesis and Evaluation of Genistein-polyamine Conjugates as Multi-functional Anti-Alzheimer Agents

An efficient and promising method to prepare Ladostigil (TV3326) via asymmetric transfer hydrogenation catalyzed by Ru–Cs-DPEN in an HCOONa–H2O–surfactant system

The enantiopure multi-functional anti Alzheimer’s drug, Ladostigil (TV3326), was prepared by using asymmetric transfer hydrogenation (ATH) as a key step catalyzed by Ru–Cs-DPEN in an HCOONa–H2O–surfactant system. Good chemical yields with high enantiomeric excess were obtained and the catalyst could be recycled another five times.

Promising multifunctional anti-Alzheimer's dimer bis(7)-Cognitin acting as an activator of protein kinase C regulates activities of α-secretase and BACE-1 concurrently

We have recently demonstrated that bis(7)-Cognitin, a promising multifunctional anti-Alzheimer 's dimer, can remarkably reduce the generation of amyloid β peptide (Aβ) by inhibiting β-secretase (BACE-1) and activating α-secretase activity. In this study, the mechanism(s) underlying bis(7)-Cognitin 's regulation of the activity of these two proteases was further investigated. In N2a cells stably expressing human amyloid precursor protein with the Swedish mutation (APPswe), the reduction in Aβ production induced by 1 μM bis(7)-Cognitin was not altered by the co-pretreatment of muscarinic and nicotinic cholinergic receptor antagonists, indicating that the regulation of APP processing by this dimer is independent of cholinergic transmission. Furthermore, bis(7)-Cognitin (0.1–3 μM) significantly increased protein kinase C (PKC) activity in cells and in vitro in a concentration-dependent manner. Administration of a PKC activator, phorbol 12-myristate 13-acetate (PMA), concentration-dependently increased the α-secretase cleavage products, and reduced the BACE-1 cleavage products. In addition, the inhibition of PKC prevented PMA- or bis(7)-Cognitin-induced alterations in α-secretase and BACE-1 activities, eliminating reductions in Aβ production seen with PMA or the dimer. These results strongly suggest that bis(7)-Cognitin may reduce the biosynthesis of Aβ by inhibiting BACE-1 and activating α-secretase concurrently through the direct activation of PKC. Combined with previous findings of direct inhibition of AChE and BACE-1 by this dimer, this work indicates that strategy may have potential to provide new insights into designing novel drugs that target multiple steps of aberrant APP processing to treat Alzheimer 's disease.

Novel Multifunctional Anti-Alzheimer Drugs with Various CNS Neurotransmitter Targets and Neuroprotective Moieties

Traditionally, drug design programs are focused on optimizing the specificity of lead compounds against a carefully selected drug target. Disappointingly, this approach to discover a "magic bullet" drug has not met with the expected success for CNS disorders. Transcriptomics and proteomic profiling of neurodegenerative diseases have indicated that they are poly-etiological in origin and that the processes leading to neuronal death are multifactorial. An emerging concept is the design of drug ligands that modulate multiple drug targets identified for a particular disease. In this review we explore some examples of multifunctional drugs which may be useful in the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.