Cholinesterase Inhibitors Research Articles

Impact of type 2 diabetes and its duration on incidence rates of dementia death and medication prescription in the Australian population during 2003–2016

AimsTo quantify rates of dementia treatment and death among Australians with type 2 diabetes relative to those without diabetes using linked national registries of Australia. MethodsThe study included 891,418 people with type 2 diabetes registered on the National Diabetes Services Scheme and a randomly sampled, population-based comparison group (n = 1,131,369). Outcomes included dementia death (all-cause dementia, Alzheimer’s disease (AD) or vascular dementia), and first prescription of cholinesterase inhibitors or memantine. ResultsExcess dementia risk was observed in the diabetes group for the composite outcome of all-cause dementia death or dementia medication prescription but varied with age at diabetes diagnosis and its duration. At age 70, the rate of dementia death/medication prescription was ∼1.3 (95% CI 1.2, 1.3) and 1.1 (95% CI 1.1, 1.2) times higher in people with ten and five years of diabetes duration, respectively. Individual outcomes showed that diabetes was associated with a higher incidence of vascular dementia death, whereas an increased risk of AD death was only observed beyond ∼10 years of diabetes duration. Further, the incidence of dementia medication prescription was lower among people with diabetes. ConclusionsA higher incidence of AD death in the setting of 10+ years of diabetes duration coupled with a lower incidence of AD treatment suggests an under-recognition of this dementia phenotype among people with type 2 diabetes.

Glycolytic dysregulation in Alzheimer's disease: unveiling new avenues for understanding pathogenesis and improving therapy.

Alzheimer's disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative treatments. The current therapeutic strategies, primarily based on cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, offer limited symptomatic relief without halting disease progression, highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer's disease. Recent studies have provided insights into the critical role of glycolysis, a fundamental energy metabolism pathway in the brain, in the pathogenesis of Alzheimer's disease. Alterations in glycolytic processes within neurons and glial cells, including microglia, astrocytes, and oligodendrocytes, have been identified as significant contributors to the pathological landscape of Alzheimer's disease. Glycolytic changes impact neuronal health and function, thus offering promising targets for therapeutic intervention. The purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer's disease and explore the mechanisms by which these abnormalities contribute to disease onset and progression. Comprehensive focus on the pathways through which glycolytic dysfunction influences Alzheimer's disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments, emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer's disease.

A Series of Novel 1-H-isoindole-1,3(2H)-dione Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: In Silico, Synthesis and In Vitro Studies.

The derivatives of isoindoline-1,3-dione are interesting due to their biological activities, such as anti-inflammatory and antibacterial effects. Several series have been designed and evaluated for Alzheimer's therapy candidates. They showed promising activity. In this work, six new derivatives were first tested in in silico studies for their inhibitory ability against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Molecular docking and molecular dynamic simulation were applied. Next, these compounds were synthesized and characterized by 1H NMR, 13C NMR, FT-IR, and ESI-MS techniques. For all imides, the inhibitory activity against AChE and BuChE was tested using Ellaman's method. IC50 values were determined. The best results were obtained for the derivative I, with a phenyl substituent at position 4 of piperazine, IC50 = 1.12 μM (AChE) and for the derivative III, with a diphenylmethyl moiety, with IC50 = 21.24 μM (BuChE). The compounds tested in this work provide a solid basis for further structural modifications, leading to the effective design of potential inhibitors of both cholinesterases.

Synthesis and Biological Evaluation of Colchicine─Aryl/Alkyl Amine Hybrids as Potential Noncytotoxic Cholinesterase Inhibitors: Identification of SBN-284 as a Dual Inhibitor of Cholinesterases and NLRP3 Inflammasome.

Colchicine, one of the oldest anti-inflammatory natural products still used clinically, inhibits NF-κB signaling and NLRP3 inflammasome activation. Despite its cytotoxicity and narrow therapeutic range, colchicine continues to intrigue medicinal chemists exploring its anti-inflammatory potential. This study aimed to investigate the colchicine scaffold for its role in Alzheimer's disease by targeting neuroinflammation and cholinesterases. Molecular docking revealed that colchicine's hydrophobic trimethoxyphenyl framework can potentially bind to the peripheral anionic site of cholinesterases. Hybrid structures combining colchicine with aryl/alkyl amines were designed to bind both peripheral and catalytic sites of cholinesterases. We describe here the design, synthesis, and in vitro cytotoxicity evaluation of these colchicine-aryl/alkyl amine hybrids, along with their in silico interactions with the cholinesterase active site gorge. Nontoxic analogs demonstrating strong cholinesterase binding affinity were further evaluated for their anticholinesterase and antineuroinflammatory activities. The colchicine-donepezil hybrid, SBN-284 (3x), inhibited both acetylcholinesterase and butyrylcholinesterase as well as the NLRP3 inflammasome complex at low micromolar concentrations. It achieved this through noncompetitive inhibition, occupying the active site gorge and interacting with both peripheral and catalytic anionic sites of cholinesterases. Analog 3x was shown to cross the blood-brain barrier and exhibited no toxicity to neuronal cells, primary macrophages, or epithelial fR2 cells. These findings highlight the potential of this lead compound for further preclinical investigation as a promising anti-Alzheimer agent.

Advances in tacrine for Alzheimers disease

Alzheimers disease is a kind of neurodegenerative disease with insidious and progressive onset, which will affect the normal life of patients to varying degrees. At present, there is no specific drug that can completely cure Alzheimers disease, and there is still a long way to go in the treatment of the disease. In order to provide better ideas for the development of drugs to treat Alzheimers disease, people have speculated and verified a variety of pathogenesis of the disease as far as possible and developed targeted drugs on this basis. In addition to the need to develop drugs from multiple pathogenetic perspectives, it is also necessary to conduct longitudinal studies on one drug. Since tachrine is one of the drugs with great development potential, this paper will take Tachrine, a representative of cholinesterase inhibitors, as the main drug research object, analyze the structure and efficacy of various existing tachrine drugs, and try to provide the future development direction of Tachrine drug transformation.

Design, synthesis and anti-Alzheimer's disease activity evaluation of C-3 arylated huperzine A derivatives

A series of C-3 arylated huperzine A (HPA) derivatives (1−30) were designed and synthesized in good yields via palladium-catalyzed Suzuki cross-coupling reaction. Cholinesterase inhibitory and neuroprotective activities of all 30 derivatives were evaluated. Cholinesterase inhibition results revealed that derivatives 2 and 15 exhibited dual inhibitory activity against both acetylcholinesterase (AChE inhibition: 2, IC50 = 1.205 ± 0.395 μM; 15, IC50 = 0.225 ± 0.062 μM) and butyrylcholinesterase (BChE inhibition: 2, IC50 = 8.598 ± 3.605 μM; 15, IC50 = 4.013 ± 0.068 μM), a feature not observed in huperzine A. Molecular docking results indicated that the introduction of aryl groups enhanced the affinity of the derivatives for the acyl-binding pocket of BChE, thereby limiting the hydrolysis of acetyl choline. However, these derivatives exhibited poor performance in cytotoxicity and neuroprotection assays.

Chiral thioureas containing naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, cholinesterase inhibition activity and molecular docking studies

Butyrylcholinesterase (BChE), which plays a role in the regulation of acetylcholine (ACh) as well as cholinergic type neurotransmission, also has non-cholinergic functions such as differentiation, proliferation and apoptosis. The strategy of increasing ACh levels without the typical undesirable effects of AChE inhibitors used in treatment with selective inhibition of BChE may be an effective approach to delay the progression of Alzheimer's disease (AD). Based on this approach, twenty derivatives of chiral thioureas containing the naphthalene moiety (1a-10a and 1b-10b) in both enantiomeric forms were designed, synthesized with good yields (up to 90 %), in this study. Also, their AChE and BChE inhibition activities and antioxidant profiles were tested. All chiral thioureas except compound 5b showed excellent inhibitory activity against BChE but lower inhibitory activity against AChE compared to galantamine. The activity results on BChE revealed that compound 1b (S-enantiomer) had the strongest inhibitory effect on BChE (IC50 = 10.18 ± 1.02 μM) with a selectivity index of 7.27 among all compounds. In terms of antioxidant activity, compound 7a (R-isomer) exhibited the overall highest antioxidant profile in the series of chiral thioureas. Molecular docking studies were used to reveal the interactions of the most active compounds with target enzymes. Besides, an estimation of the drug-likeness and pharmacokinetic properties of all chiral thioureas was performed.

Synthesis and cholinesterases inhibitory effects of water soluble zinc(II) and silicon(IV) phthalocyanines bearing ({8‐[3‐(dimethylamino)phenoxy]octyl}oxy) groups

Alzheimer's disease, is one of the irreversible neurodegenerative disorders among older people, causes behavior, memory, and thinking problems. This study aim is to synthesize of 4‐({8‐[3‐(dimethylamino)phenoxy]octyl}oxy)phthalonitrile, zinc(II) phthalocyanine and its water soluble derivative containing ({8‐[3‐(dimethylamino)phenoxy]octyl}oxy) substituents at the peripheral positions first time. To determine the potential of water soluble silicon(IV) and zinc(II) phthalocyanines for use in AD, spectrophotometric assays were performed to determine their acetylcholinesterase/butyrylcholinesterase inhibitory effects. In addition, their DNA nuclease properties were evaluated by agarose gel electrophoresis. The results showed that the compounds inhibited acetylcholinesterase/butyrylcholinesterase. They did not damage pBR322 plasmid DNA depending on time and concentration. As a result of the experiments, it is revealed that the compounds may be the potential for use as cholinesterase inhibitors, which is a promising approach for the treatment of Alzheimer's disease.

Barbiturate-sulfonate hybrids as potent cholinesterase inhibitors: design, synthesis and molecular modeling studies.

Aim: Design and synthesis of a series of 5-benzylidene(thio)barbiturates 3a-r.Methodology: Evaluation of the inhibitory activity of the new chemical entities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Donepezil as the standard reference.Results & Conclusion: Compound 3r emerged as the most potent AChE inhibitor (IC50=9.12μM), while compound 3q exhibited the highest inhibitory activity against BChE (IC50=19.43μM). Toxicological bioassays confirmed the absence of cytotoxicity for the most potent compounds at the tested doses. Molecular docking analysis demonstrated that the tested derivatives effectively bind to the active sites of both enzymes. Overall, this study sheds light on the potential of barbiturate-sulfonate conjugates as promising drug candidates.

Advances of therapy for Alzheimer's disease: An updated review

AbstractAlzheimer's disease (AD) is a type of dementia characterized by a decline in brain function, which leads to the inability to perform activities independently. Many researchers recognize abnormalities related to beta‐amyloid as the main cause of the disease (i.e., the beta‐amyloid hypothesis), but aging, genetics, coronary heart disease, environmental factors, gender, and other risk factors may also contribute to AD development. Three drugs with different mechanisms are available for AD treatment: cholinesterase inhibitors, N‐methyl d‐aspartate, and aducanumab. This study reviewed the therapies that are already applied in clinical practice and those that are currently being investigated for clinical use. These therapies include not only pharmacological treatments but also non‐pharmacological treatments, such as gut flora therapy and music therapy. A comprehensive understanding of these therapies is necessary to enable early intervention, improve patients' physical and mental conditions, delay the occurrence and development of AD, and extend patients' healthy lifespans.

Review on Alzheimer’s disease

The treatment of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) is crucial for individuals with the condition. Cholinesterase inhibitors (CIs) and memantine, used for cognitive symptoms, may have some effect on BPSD, but additional drugs may be needed as BPSD worsens. Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, sertraline, and others are effective antidepressants for comorbid depression in AD. Limited evidence supports their use for treating depression, agitation, and psychosis in AD, but recent trials showed no benefit and increased risks. Non-pharmacological interventions such as psycho social approaches and alternative therapies are important. A comprehensive approach combining medication and non-pharmacological interventions, along with close monitoring, is essential for managing BPSD and improving quality of life for individuals with AD and their caregivers.

Potential nanomedicinal applications and physicochemical nature of Hyphaene thebaica-reduced nano-samaria.

Herein we described the biofabrication of samarium oxide nanoparticles (HT-Sm2O3 NPs) by applying the aqueous fruit extract of Hyphaene thebaica was utilized as an eco-friendly chelating agent. The prepared NPs were subjected to various physicochemical properties and potential in biomedical applications. X-ray Diffraction (XRD) pattern revealed sharp peaks that corroborated with the Joint Committee on Powder Diffraction Standards (JCPDS) card no. 00-042-1464. Crystallite size obtained from Debye-Scherrer approximation and Williamson-Hall (W-H) plot was 28.73 and 69.3 nm, respectively. Optical bandgap was calculated by employing Kubelka-Munk (K-M) function and was found to be ~4.58 eV. Raman shift was observed at 121, 351, 424-, and 561 cm-1. Photoluminescence (PL) spectra revealed two major peaks positioned at 360 and 540 nm. The high-resolution transmission electron microscopy (HR-TEM) analysis of HT-Sm2O3 nanoparticles (NPs) showed that they predominantly have spherical to cuboidal shapes. Additionally, the selected area electron diffraction (SAED) pattern presented spotty rings, indicating a high level of crystallinity in these NPs. The potential nanomedicine applications were studied using diverse bioassays using different treatments. The antioxidant activity demonstrated 45.71% ± 1.13% inhibition at 1000 μg/mL. Brine shrimp lethality assay revealed the highest cytotoxicity of 46.67% ± 3.33% at 1000 μg/mL and LC50 value of 1081 μg/mL. HT-Sm2O3 NPs exhibited inhibition of angiogenesis (20.41% ± 1.18%) at of 1000 μg/mL. MTT assay results indicated that HT-Sm2O3 NPs exhibit inhibitory effects on cell lines. Specifically, these NPs showed an IC50 value of 104.6 μg/mL against 3T3 cells. Against MCF-7 cells, the NPs demonstrated an IC50 value of 413.25 μg/mL. Additionally, in the inhibition of acetylcholinesterase (AChE), the newly synthesized NPs showed an IC50 value of 320 μg/mL. The antidiabetic assessment through α-glucosidase and α-amylase inhibition assays revealed, an IC50 value of 380 μg/mL for α-glucosidase and 952 μg/mL for α-amylase was calculated. Overall, our study suggested that the Sm2O3 NPs possess moderate anticancer, cholinesterase inhibition, and antidiabetic potential, however, needs further assessment. RESEARCH HIGHLIGHTS: In this work, nano-samaria is synthesized using an eco-friendly and green approach. The nanoparticles were characterized using techniques such as Raman, HR-TEM, FTIR, DRS, XRD, and so on, and the applications were studied using multiple in vitro bioassays for Diabetes, Alzheimer, and Cancer. The nano-samaria revealed good potential for potential biomedical applications.

Screening cholinesterase inhibitory potential of selected amines

Cholinesterase inhibition has gained attention in the treatment of some disease states, covering cholinergic deficiency. Alzheimer’s disease (AD) can be counted as the most important one among them. Indeed, the current drugs used in the treatment of AD are cholinesterase inhibitor molecules, besides memantine, and biological new drugs. Many pharmacophores have been suggested so far for cholinesterase inhibition and many of them possess a basic center with an amine function. Within this work, we have selected some simple amines and investigated their potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes. The results indicated that simple amines by themselves don’t have strong potential unless they are used with other pharmacophores.

Cholinesterase Inhibition and Antioxidative Capacity of New Heteroaromatic Resveratrol Analogs: Synthesis and Physico-Chemical Properties.

The targeted compounds in this research, resveratrol analogs 1-14, were synthesized as mixtures of isomers by the Wittig reaction using heterocyclic triphenylphosphonium salts and various benzaldehydes. The planned compounds were those possessing the trans-configuration as the biologically active trans-resveratrol. The pure isomers were obtained by repeated column chromatography in various isolated yields depending on the heteroaromatic ring. It was found that butyrylcholinesterase (BChE) was more sensitive to the heteroaromatic resveratrol analogs than acetylcholinesterase (AChE), except for 6, the methylated thiophene derivative with chlorine, which showed equal inhibition toward both enzymes. Compounds 5 and 8 achieved the highest BChE inhibition with IC50 values of 22.9 and 24.8 μM, respectively. The same as with AChE and BChE, methylated thiophene subunits of resveratrol analogs showed better enzyme inhibition than unmethylated ones. Two antioxidant spectrophotometric methods, DPPH and CUPRAC, were applied to determine the antioxidant potential of new heteroaromatic resveratrol analogs. The molecular docking of these compounds was conducted to visualize the ligand-active site complexes' structure and identify the non-covalent interactions responsible for the complex's stability, which influence the inhibitory potential. As ADME properties are crucial in developing drug product formulations, they have also been addressed in this work. The potential genotoxicity is evaluated by in silico studies for all compounds synthesized.

N-Glycosylation Deficiency in Transgene α7 nAChR and RIC3 Expressing CHO Cells Without NACHO.

The human neuronal nicotinic acetylcholine receptor α7 (nAChR) is an important target implicated in diseases like Alzheimer's or Parkinson's, as well as a validated target for drug discovery. For α7 nAChR model systems, correct folding and ion influx functions are essential. Two chaperones, resistance to inhibitors of cholinesterase 3 (RIC3) and novel nAChR regulator (NACHO), enhance the assembly and function of α7 nAChR. This study investigates the consequence of NACHO absence on α7 nAChR expression and function. Therefore, the sequences of human α7 nAChR and human RIC3 were transduced in Chinese hamster ovary (CHO) cells. Protein expression and function of α7 nAChR were confirmed by Western blot and voltage clamp, respectively. Cellular viability was assessed by cell proliferation and lactate dehydrogenase assays. Intracellular and extracellular expression were determined by in/on-cell Western, compared with another nAChR subtype by novel cluster fluorescence-linked immunosorbent assay, and N-glycosylation efficiency was assessed by glycosylation digest. The transgene CHO cell line showed expected protein expression and function for α7 nAChR and cell viability was barely influenced by overexpression. While intracellular levels of α7 nAChR were as anticipated, plasma membrane insertion was low. The glycosylation digest revealed no appreciable N-glycosylation product. This study demonstrates a stable and functional cell line expressing α7 nAChR, whose protein expression, function, and viability are not affected by the absence of NACHO. The reduced plasma membrane insertion of α7 nAChR, combined with incorrect matured N-glycosylation at the Golgi apparatus, suggests a loss of recognition signal for lectin sorting.

Pharmacokinetic and molecular docking studies to pyrimidine drug using Mn3O4 nanoparticles to explore potential anti-Alzheimer activity

Alzheimer disease (AD) is the cause of dementia and accounts for 60–80% cases. Tumor Necrosis Factor-alpha (TNF-α) is a multifunctional cytokine that provides resistance to infections, inflammation, and cancer. It developed as a prospective therapeutic target against multiple autoimmune and inflammatory disorders. Cholinergic insufficiency is linked to Alzheimer's disease, and several cholinesterase inhibitors have been created to treat it, including naturally produced inhibitors, synthetic analogs, and hybrids. In the current study, we tried to prepared compounds may also support the discovery and development of novel therapeutic and preventative drugs for Alzheimer's using manganese tetroxide nanoparticles (Mn3O4-NPs) as a catalyst to generate compounds with excellent reaction conditions. The Biginelli synthesis yields 4-(4-cyanophenyl)-6-oxo-2-thioxohexahydropyrimidine-5-carbonitrile when the 4-cyanobenzaldehyde, ethyl cyanoacetate, and thiourea were coupled with Mn3O4-NPs to produce compound 1. This multi-component method is non-toxic, safe, and environmentally friendly. The new approach reduced the amount of chemicals used and preserved time. Compound 1 underwent reactions with methyl iodide, acrylonitrile, chloroacetone, ethyl chloroacetate, and chloroacetic acid/benzaldehyde, each of the synthetized compounds was docked with TNF-α converting enzyme. These compounds may also support the discovery and development of novel therapeutic and preventative drugs for Alzheimer's disease. The majority of the produced compounds demonstrated pharmacokinetic features, making them potentially attractive therapeutic candidates for Alzheimer's disease treatment.

Chemical composition, anticholinesterase activity, and molecular docking studies of Piper baccatum Blume (Piperaceae) essential oil

Piper baccatum is a woody climber and grows throughout the tropics mostly in Southeast Asia such as Thailand, Malaysia, Singapore, and Indonesia. The studies on essential oil composition and anticholinesterase activities were performed, along with molecular docking of all components. The essential oil was obtained by hydrodistillation and analyzed by GC-FID and GC-MS, while anticholinesterase activity was assessed using Ellman method. A total of 14 components were identified, representing 98.1% of the total composition of the essential oil. The major identified components were β-caryophyllene (30.7%), camphene (22.1%), eucalyptol (14.9%), γ-muurolene (6.9%), and α-pinene (5.3%). A moderate inhibitory effect was observed for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of 80.5 and 96.4 μg/mL, respectively. Molecular docking studies of P. baccatum components with AChE and BChE revealed binding energy ranges of -5.6 to -8.5 Kcal/mol and -5.2 to -7.8 Kcal/mol, respectively, predominantly involving hydrophobic interactions with active site residues. Notably, β-caryophyllene and γ-muurolene exhibited superior binding energy profiles with both AChE and BChE compared to other components. The docking results underscore the potential of P. baccatum essential oil components as cholinesterase inhibitors, with implications for applications in food, aromatherapy, and pharmaceutical industries. The identified components, particularly β-caryophyllene and γ-muurolene, showcase promising attributes for further exploration in developing therapeutic interventions targeting cholinesterase-related conditions. This essential oil in general could be potentially used as a cholinesterase inhibitor with possible applications in food, aromatherapy, and pharmaceutical industries.

L-carnitine: A novel approach in management of acute cholinesterase inhibitor insecticide poisoning.

Cholinesterase inhibitors (ChEIs) insecticide poisoning is a serious global health concern that results in hundreds of thousands of fatalities each year. Although inhibition of the cholinesterase enzyme is the main mechanism of ChEI poisoning, oxidative stress is considered the mechanism underlying the related complications. The study aimed to assess the oxidative status of the patients with ChEI insecticide poisoning and the role of L-carnitine as adjuvant therapy in their management. Human studies on the efficacy and safety of L-carnitine in treating insecticide poisoning are limited despite its growing research interest as a safe antioxidant. This prospective study was conducted on eighty patients with acute ChEIs insecticide poisoning admitted to Alexandria Poison Center, Alexandria Main University Hospital, Egypt. Patients were allocated into two equal groups randomly. The L-carnitine (LC) group received the conventional treatment (atropine & toxogonin) and LC and the standard treatment (ST) group received the standard treatment only. Outcome measures were fatality rate, the total administered dose of atropine & toxogonin, length of hospital stay, and the requirement for ICU admission or mechanical ventilation. The study results revealed that malondialdehyde (MDA) significantly decreased in the LC group. Cholinesterase enzyme levels increased significantly after treatment in the LC group than in the ST group. The LC group needed lower dosages of atropine and toxogonin than the ST group. Also, the LC group showed no need for ICU admission or mechanical ventilation. The study concluded that LC can be considered a promising adjuvant antioxidant treatment in acute ChEIs pesticide poisoning.

Systematic Review on Pathology and Drug Efficacy Clinical Trials (1973-2023) for Cognitive Impairment and Alzheimer’s Dementia

Rationale: The systematic review evaluates the results of last fifty years (1973-2023) of clinical trials on pathology and treatment for cognitive impairment including Alzheimer’s dementia (AD dementia). Objectives: Alzheimer’s dementia is a growing public health concern worldwide. The systematic review analyzes the disease confirming pathological findings presented by modern imaging techniques MRI/ PET. In addition, we analyze the success of fifty years of therapeutic advancements of the neurological disabilities and count on the safe drugs to treat clinical conditions of AD dementia. Findings: We followed the PRISMA guidelines to determine the inclusion and exclusion criteria for the selection of clinical records collected from the NCBI databases. We analyzed the drug efficacy results on the three aspects of the AD brain: (a) morphological deformation of the choroid plexus and hippocampus; (b) senile plaques with amyloid beta42 (Abeta42) including hyperintensities of neurons; and (c) inhibitory action of acetylcholinesterase enzyme. The pathological findings include detection of Abeta42 plaques in cerebral cortex and retention ability of trial drugs in cerebrospinal fluid versus blood plasma of AD patients in the context of disease progression and treatment efficacy. The clinical trial records demonstrated evidence of genetic susceptibility factor(s) clustered in European populations. The susceptibility is also found due to mutations in the presenilin-1 gene and expression of the ApoEε-allele among the population. The clinical records demonstrate moderate efficacy of cholinesterase inhibitors Donepezil and Rivastigmine in improving cognition. The antibodies aducanumab, donanemab, and lecanemab show low to moderate success in removing plaques and reducing plasma Abeta burden. Conclusion: The cholinesterase inhibitors demonstrate moderate success in improving cognition. However, the overall efficacy of antibody treatment was poor. The findings suggest a need for new generation drugs which can clear plaques and improve cognition for AD.

Cholinesterase inhibitors for the treatment of Alzheimer’s disorder: Synthesis, biological analysis and molecular modelling studies of iso-quinoline derivatives

The most difficult issue nowadays is Alzheimer’s, particularly in developing nations. Targeting the associated enzymes is most efficient way for new drug development. We synthesized isoquinoline analogues (1–13) against acetylcholinesterase and butyrylcholinesterase. With respect to acetylcholinesterase, the range of inhibitory activity (IC50) for each analogue was 0.10 ± 0.05 to 11.10 ± 0.30 μM, and for butyrylcholinesterase, it was 0.30 ± 0.05 to 20.30 ± 0.40 μM. Compounds 2, 7, 9, 11, 12, and 13 showed excellent inhibition, with IC50 values of 2.30 ± 0.10, 0.30 ± 0.05, 2.70 ± 0.10, 1.05 ± 0.10, 1.40 ± 0.10, and 2.70 ± 0.10 μM, respectively. The butyrylcholinesterase activity of all analogues was good. Structure activity relationship (SAR) has been established for all newly synthesized derivatives. Molecular docking studies were carried out to understand the binding interactions with enzyme active sites.