Anticholinesterase Drugs Research Articles

Influence of Anticholinesterase Drugs on Activity and Properties of Na+,K+-ATPase in Rat Erythrocytes under Stress Caused by Intense Physical Exercise.

We studied the effect of intramuscular injection of physostigmine and neostigmine on Na+,K+-ATPase activity in erythrocytes of rats subjected to intense physical exercise. Both anticholinesterase drugs had a significant effect on the development of the stress response, which was expressed in a decrease in the manifestation of its individual components such as the concentration of ascorbic acid in the adrenal glands, stress-related erythrocyte polycythemia, and LPO indicators. Anticholinesterase drugs reverse the stress-induced decrease in Na+,K+-ATPase activity, as well as changes in its magnesium-dependent properties. There were no changes in the activity of the studied enzyme in the erythrocyte ghosts. We associate the observed differences with the correction of the functions of the cholinergic components of the hypothalamic-pituitary-adrenal axis leading to the development of a hypoergic type stress reaction.

Synthesis and characterization of tannic acid–copper complex: A promising anticholinesterase drug

This study aimed to present an optimized synthetic pathway for a complex formed between copper (II) metal ion and tannic acid (TA), which have a variety of pharmacological properties. The study also focused on characterizing this metallodrug, carrying out in vitro antioxidant and acetylcholinesterase enzyme (AChE) inhibition assays, and performing in vivo toxicity assay against zebrafish (Danio rerio), thus expanding the area of study involving syntheses of metal complexes to act as therapeutic agents. Through various characterization techniques, including UV–Vis Absorption Spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), Thermal Analysis (TG and DTG), 1H Nuclear Magnetic Resonance (1H NMR), Inductively Coupled Plasma with Optical Emission Spectrometry (ICP-OES), and Electron Paramagnetic Resonance (EPR), it was confirmed that the metal ion is coordinated to the ligand, exhibiting distorted planar square geometry with mononuclear copper (3.10 ± 0.10 % copper by ICP-OES). In vitro tests demonstrated that the TA–Cu complex presents antioxidant activity against DPPH (IC50 = 2.26 ± 0.01 µg mL−1) and ABTS (IC50 = 1.91 ± 0.07 µg mL−1) radical scavenging assays. These results were more promising than those obtained for the TA (4.25 ± 0.03 µg mL−1 and 3.37 ± 0.03 µg mL−1, respectively). In the in vitro inhibition of AChE assay, the TA–Cu complex (4.07 ± 0.04 µg mL−1) presented a lower IC50 value than TA (5.80 ± 0.09 µg mL−1), indicating that coordination to the metal center Cu (II) was able to improve the anticholinesterase activity of the free ligand. Furthermore, the TA–Cu complex did not show toxicity in the in vivo test with adult zebrafish for 96 h at the tested doses of 4–40 mg kg−1, with LD50 >40 mg kg−1. Thus, it is estimated that the TA–Cu complex is a metallodrug with anticholinesterase potential, representing a promising strategy for conducting future pre-clinical studies in models of Alzheimer’s disease.

Analysis of drugs' use for the treatment of dementia in psychiatry

BACKGROUND: The article provides an analysis of the prescriptions of a group of medications used for the prevention and treatment of dementia associated with central nervous system damage. During the period of gerontogenesis, irreversible changes occur in the human body, associated with the somatic state and mental processes in the CNS. According to the ICD-11 classification, this type of pathology is defined as neurocognitive disorders (6D80-86). PURPOSE OF THE STUDY: Analysis of the prescription of drugs for the treatment of dementia in patients with disorders caused by neurocognitive changes due to the aging process. MATERIALS AND METHODS: In the course of the study, the following were used: content analysis, observation method, documentary, systematic, statistical and other methods of analyzing drug prescriptions. The research base include the gerontological departments of the Sverdlovsk Regional Psychiatric Hospital. Medical documentation with the specified medications prescribed to patients aged 60 years and older with a psychiatric history. RESULTS AND DISCUSSION: A trend has been established towards a decrease in the number of prescriptions of drugs No. 1–3, 7 (Galantamine, Memantine, Akineton and Vinpocetine, respectively) and an increase in No. 4–6 (aminophenylbutyric acid, rivastigmine, piracetam). The experts prefer drugs with nootropic effects (57% of the entire sample), which are used along with anticholinergics (14%) and anticholinesterase drugs (29%). CONCLUSION: According to the results of the analysis, a high level of prescriptions by doctors of specialized departments have medicines numbered No. 4, 5, and 6 (aminophenylbutyric acid, rivastigmine, piracetam).

Therapeutic challenges and unmet needs in the management of myasthenia gravis: an Italian expert opinion.

Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs.

Electrochemical Acetylcholinesterase Sensors for Anti-Alzheimer's Disease Drug Determination.

Neurodegenerative diseases and Alzheimer's disease (AD), as one of the most common causes of dementia, result in progressive losses of cholinergic neurons and a reduction in the presynaptic markers of the cholinergic system. These consequences can be compensated by the inhibition of acetylcholinesterase (AChE) followed by a decrease in the rate of acetylcholine hydrolysis. For this reason, anticholinesterase drugs with reversible inhibition effects are applied for the administration of neurodegenerative diseases. Their overdosage, variation in efficiency and recommendation of an individual daily dose require simple and reliable measurement devices capable of the assessment of the drug concentration in biological fluids and medications. In this review, the performance of electrochemical biosensors utilizing immobilized cholinesterases is considered to show their advantages and drawbacks in the determination of anticholinesterase drugs. In addition, common drugs applied in treating neurodegenerative diseases are briefly characterized. The immobilization of enzymes, nature of the signal recorded and its dependence on the transducer modification are considered and the analytical characteristics of appropriate biosensors are summarized for donepezil, huperzine A, rivastigmine, eserine and galantamine as common anti-dementia drugs. Finally, the prospects for the application of AChE-based biosensors in clinical practice are discussed.

Profiling Novel Quinuclidine-Based Derivatives as Potential Anticholinesterase Drugs: Enzyme Inhibition and Effects on Cell Viability.

The cholinergic system, relying on the neurotransmitter acetylcholine (ACh), plays a significant role in muscle contraction, cognition, and autonomic nervous system regulation. The enzymes acetylcholinesterase, AChE, and butyrylcholinesterase, BChE, responsible for hydrolyzing ACh, can fine-tune the cholinergic system's activity and are, therefore, excellent pharmacological targets to address a range of medical conditions. We designed, synthesized, and profiled 14 N-alkyl quaternary quinuclidines as inhibitors of human AChE and BChE and analyzed their impact on cell viability to assess their safety in the context of application as potential therapeutics. Our results showed that all of the 14 tested quinuclidines inhibited both AChE and BChE in the micromolar range (Ki = 0.26 - 156.2 μM). The highest inhibition potency was observed for two bisquaternary derivatives, 7 (1,1'-(decano)bis(3-hydroxyquinuclidinium bromide)) and 14 (1,1'-(decano)bis(3-hydroxyiminoquinuclidinium bromide)). The cytotoxic effect within 7-200 μM was observed only for monoquaternary quinuclidine derivatives, especially those with the C12-C16 alkyl chain. Further analysis revealed a time-independent mechanism of action, significant LDH release, and a decrease in the cells' mitochondrial membrane potential. Taking all results into consideration, we can confirm that a quinuclidine core presents a good scaffold for cholinesterase binding and that two bisquaternary quinuclidine derivatives could be considered as candidates worth further investigations as drugs acting in the cholinergic system. On the other hand, specific cell-related effects probably triggered by the free long alkyl chain in monoquaternary quinuclidine derivatives should not be neglected in future N-alkyl quaternary quinuclidine derivative structure refinements. Such an effect and their potential to interact with other specific targets, as indicated by a pharmacophore model, open up a new perspective for future investigations of these compounds' scaffold in the treatment of specific conditions and diseases other than cholinergic system-linked disorders.

Routing, diagnosis and treatment of adult patients with facial nerve neuropathy in the metropolis

The diversity and inconsistency of the proposed tactics for diagnosing and treating patients with facial nerve neuropathy (FNN) can cause difficulties for neurologists in their daily routine work.Aim. To analyze the routing of patients with FNN, the clinical practice of diagnostic studies and medical care in polyclinics and hospitals in Moscow.Material and methods. Analysis of data from the EMIAS system from polyclinics and hospitals in Moscow based on 7344 cases of primary treatment of patients with a diagnosis of FNN for 2019–2021: Gr1 — idiopathic (n = 4265), Gr2 — symptomatic (n = 3079), with the definition of patient routing, volume of diagnosis and treatment.Results. Gr1 patients visit the polyclinic (61.6%) on 8th [3; 20] day from the onset of symptoms, Gr2 — on 10th [3; 28.2]; to the hospital (38.4%) — on 1st [0; 3]. Clinical examination is variable, mainly the primary manifestations of FNN are indicated by the method of describing the deficiency. Laboratory diagnostics includes a clinical blood test (8%), the search for a viral or other cause (in isolated cases). Magnetic resonance imaging is done in different regimes (even in Gr1), only in 1/4 of cases with contrast. Recommended consultations of an otorhinolaryngologist, an ophthalmologist, rarely — doctors of surgical specialties, an exercise therapy doctor, a psychologist. The volume of diagnostics is greater in the hospital (p < 0,001). The list of drug therapy varies from evidence-based drugs to homeopathic remedies. In the polyclinic, 2/3 of the specialists prescribe the dose of prednisolone in accordance with foreign clinical recommendations, in the hospital — 1/2 (x2 = 4,83; p = 0.028). However, every second case goes beyond the “therapeutic window” due to the late visit of the patient. The most commonly used vitamins of group B (32.5%), anticholinesterase drugs (28.9%), thioctic acid (15.5%). Antiviral drugs were prescribed in 2% of cases, in the polyclinic eye care measures — less than 2%, in the hospital — 20%. Non-drug treatment includes physical therapy (21.8%), physiotherapy (14.2%), acupuncture (6.4%), facial massage (2.9%), tape correction (1.9%).Conclusions. Differences in approaches to the diagnosis, treatment and routing of patients with FNN were found. The problem can be solved by creating Russian clinical guidelines, including a unifi ed protocol for clinical examination, laboratory and instrumental diagnostics

1,2,3-Triazolo[4,5-b]aminoquinolines: Design, synthesis, structure, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, and molecular docking of novel modified tacrines

An efficient [4 + 2] cyclization protocol to synthesize a series of twelve examples of 1,2,3-triazolo[4,5-b]aminoquinolines (5) as novel structurally modified tacrines was obtained by reacting readily accessible precursors (i.e., 3-alky(aryl)-5-amino-1,2,3-triazole-4-carbonitriles (3)) and selected cycloalkanones (4) of five-, six-, and seven-membered rings. We evaluated the AChE and BChE inhibitory activity of the novel modified tacrines 5, and the compound derivatives from cyclohexanone (4b) showed the best AChE and BChE inhibitory activities. Specifically, 1,2,3-triazolo[4,5-b]aminoquinolines 5bb obtained from 3-methyl-carbonitrile (3b) showed the highest AChE (IC50 = 12.01 μM), while 5ib from 3-sulfonamido-carbonitrile (3i) was the most significant inhibitor for BChE (IC50 = 1.78 μM). In general, the inhibitory potency of compound 5 was weaker than the pure tacrine reference, and our findings may help to design and develop novel anticholinesterase drugs based on modified tacrines.

Validity of CSF alpha‐synuclein to predict psychosis in prodromal Alzheimer´s disease

AbstractBackgroundThe emergence of psychotic symptoms (PS) in Alzheimer´s disease (AD) involves a poor prognosis of the illness and may be related with different genetic, personal, environmental and caregiver factors, as well as unbalances in key neural proteins. In this last group, an alteration in the alpha‐synuclein (AS) metabolism may be included. Aim: To study the diagnostic validity of AS in CSF, to predict the emergence of PS in prodromal AD patients.MethodMild cognitive impairment patients (according to Petersen 2006) from the out‐patient consultation of Alicante University General Hospital (Spain) were recruited between 2010‐2018. All the patients followed NIA‐AA 2018 criteria for AD biomarkers. At inclusion, all of them had MMSE higher than 22, Neuropsychiatric Inventory lower than 10, Lawton‐Brody scale higher than 7, IQCODE lower than 80, Barthel index higher than 95 and a follow‐up higher than 2 years. All patients were treated with anticholinesterasic drugs from the diagnostic was made. The Pittsburgh sleep quality index and the Cummings criteria for psychosis (2020) were applied and the requirement of neuroleptic drugs was necessary to consider the inclusion in the psychosis group. Core AD biomarkers and AS were measured in CSF obtained in the prodromal phase of the illness. Different comparisons were made between the groups and subgroups following the time of emergence of PS.Result130 prodromal AD were included. 50 of them (38.4%) accomplished the psychosis criteria into the 8 years follow‐up. In every comparison made between groups and subgroups, AS was the best CSF biomarker to differentiate psychotic versus non psychotic groups. The level of AS 1257 pg/mL reached at least 80% of sensitivity to differentiate between both groups. A negative predictive value of 80% was found to differentiate between groups.ConclusionThe measurement of AS in CSF is the most valid biomarker used in this study to predict the emergence of PS during the 8 years after the prodromal phase of AD. These results must be confirmed in a larger population but, in our knowledge, is the first time that a CSF biomarker shows a diagnostic validity to predict PS in prodromal AD.

Validity of CSF alpha-synuclein to predict psychosis in prodromal Alzheimer's disease.

Alzheimer's disease (AD) accompanied by psychotic symptoms (PS) has a poor prognosis and may be associated with imbalances in key neural proteins such as alpha-synuclein (AS). The aim of the study was to evaluate the diagnostic validity of AS levels in the cerebrospinal fluid (CSF) as a predictor of the emergence of PS in patients with prodromal AD. Patients with mild cognitive impairment were recruited between 2010 and 2018. Core AD biomarkers and AS levels were measured in CSF obtained during the prodromal phase of the illness. All patients who met the NIA-AA 2018 criteria for AD biomarkers received treatment with anticholinesterasic drugs. Follow-up evaluations were conducted to assess patients for the presence of psychosis using current criteria; the use of neuroleptic drugs was required for inclusion in the psychosis group. Several comparisons were made, taking into account the timing of the emergence of PS. A total of 130 patients with prodromal AD were included in this study. Of these, 50 (38.4%) met the criteria for PS within an 8-year follow-up period. AS was found to be a valuable CSF biomarker to differentiate between the psychotic and non-psychotic groups in every comparison made, depending on the onset of PS. Using an AS level of 1,257 pg/mL as the cutoff, this predictor achieved at least 80% sensitivity. To our knowledge, this study represents the first time that a CSF biomarker has shown diagnostic validity for prediction of the emergence of PS in patients with prodromal AD.

Static Binding and Dynamic Transporting-Based Design of Specific Ring-Chain-Ring Acetylcholinesterase Inhibitor: From Galantamine to Natural Product.

Acetylcholinesterase (AChE) is a key target for the current symptomatic treatment of Alzheimer's disease, and galantamine is a clinical anticholinesterase drug with transiently acting characteristic and good selectivity for AChE. The present theoretical-experimental work improves the drug's residence time without reducing the inhibition effect, thus providing a crucial breakthrough for modifying the inhibitor of AChE with better kinetic behavior. The static binding and dynamic delivery properties acquired from atomic view reveal that the galantamine simply occupies a catalytic anionic site, and its release from AChE needs only ∼8.6 kcal/mol. Both of these may cause the short residence time of galantamine. The hotspots and most favorable transport mechanism are identified, and the hydrogen bond and aromatic stacking interactions are observed to play crucial roles for galantamine binding and release in AChE. The typical peripheral anionic site arisen at the delivery process would provide another key occupation to enhance the anti-release ability for inhibitors. The compound with "specific-ring-chain-ring" framework with detailed beneficial modification scheme is summarized, which may improve the residence time of the inhibitor in AChE. The thermodynamic and dynamic properties of galantamine derivatives are also studied. Based on dictamnine, a natural alkaloid, two novel eligible derivatives are designed, synthesized and evaluated, which verifies our prediction. Multiple computational approaches and experimental combinations probably provide a train of thought from both static and dynamic views to modify or design appropriate inhibitors on the basis of specific binding and transportation features.

Myasthenia gravis in current status: epidemiology, types, etiology, pathophysiology, symptoms, diagnostic tests, prevention, treatment, and complications - correspondence.

Myasthenia gravis in current status: epidemiology, types, etiology, pathophysiology, symptoms, diagnostic tests, prevention, treatment, and complications - correspondence.

Structural Scaffolds as Anti- Alzheimer Agents.

Understanding the cognitive and behavioral aspects of Alzheimer's disease- related dementia is surely a sturdy task to deal with. In recent years, a broad search for novel anti-Alzheimer agents has been continuously conducted. The malfunctioning of various neurotransmitter systems and the accumulation of abnormal proteins in the brain are the two key characteristics of this disorder. This is supported by a growing amount of evidence. Some Pharmacophoric groups/combinations exhibit potential neuroprotective activity. This study aims to compile the most recent and interesting target/target combinations/ pharmacophoric combinations to cure Alzheimer's disease. We concentrated our efforts to find the ability of certain pharmacophoric elements to interfere with various enzymatic and/or receptor systems or to work as neuroprotective agents. These pharmacophoric elements may be proved to be promising leads for future multi-target anti-Alzheimer drug discovery programs. Anticholinesterase drugs were mentioned as the best treatment thus far. Additionally, impairments in the serotonergic, GABAergic, noradrenergic, dopaminergic, and glutaminergic and a few other pathways have all been linked to memory, speech, behavioral and other alterations in Alzheimer's disease. This includes the study of workable pharmacophoric groups/combinations, receptors/ enzymatic systems and related hypotheses to find the promising therapeutic lead compounds which could work as future anti-Alzheimer drugs. We discuss future work that would improve our understanding of this Disease.

A Review on the Anesthetic Management of Patients with Neuromuscular Diseases.

Neuromuscular diseases (NMDs) are regarded as a clinically and genetically heterogeneous group of diseases characterized by weakening muscle strength and dystrophic changes in the muscle. Due to the nature of these diseases, it can be challenging for anesthesiologists to provide appropriate pain medications, symptom management, and other necessary techniques that are implemented to anesthetize the patient properly. This study was based on the available literature and the authors' experience. The current study aimed to review the available anesthesia for patients suffering from NMDs. The search process resulted in the detection of relevant articles using valid keywords on electronic databases, including Embase, PubMed, Scopus, Web of Science, and Cochrane Library. Subsequently, 19 articles published between 2009 to 2022 were identified as eligible for this review. When anesthetizing a patient with NMD, special attention should be paid to preoperative evaluation, medical-history taking, risk of difficult intubation or cardiac incidents, respiratory insufficiency, and frequent pulmonary infections. It is also necessary to keep in mind that these patients are at risk of prolonged paralysis, hyperkalemia, rigidity, malignant hyperthermia, cardiac arrest, rhabdomyolysis, or even death. Problems of anesthesia in patients with NMDs arise from the nature of the condition itself and the interaction of anesthetics and muscle relaxants with anticholinesterase drugs used in therapy. Each patient's individual risk should be assessed before anesthesia. Therefore, it is important (and even necessary before major surgery) to perform a thorough preoperative examination to not only determine perioperative risk but also to ensure optimal perioperative follow-up.

Correlations between the performance of older adults in conditional discrimination training and in a screening test for Alzheimer’s Disease

The prevalence of neurocognitive disorders has been rising and Alzheimer's Disease (AD) is the most common cause. Studies on conditional discrimination have contributed to understand the variables associated with the cognitive function. However, the relationship of such studies with cognitive impairment in older adults remains under-explored. This research aims to compare the performances of older adults during tasks involving conditional discrimination training with their performances on Addenbroke's Cognitive Examination, a widely used screening test for cognitive impairments. The sample was composed of 45 older adults. The participants performed a computerized task consisting on establishing arbitrary conditional relations between three pairs of stimuli. Addenbrooke's Cognitive Examination was administered to assess the cognitive performance. The analysis revealed a positive correlation between the performance in conditional discrimination and in the cognitive assessment. This correlation was observed only among participants who did not reported having AD in use of anti-cholinesterase drugs (30 participants). These findings demonstrate a direct relationship between learning difficulties, when it comes to learning arbitrary conditional relations, and the occurrence of cognitive decline. Therefore, the administration of the conditional relations tasks could be useful for distinguishing older adults with and without AD. Keywords: Conditional discrimination; neuropsychological tests; elderly; Alzheimer's Disease.

Peroneal nerve palsy (injury) in fibullar tunnel syndrome

While compression neuropathies of the nerves of the lower limbs are not a common pathology, peroneal nerve neuropathy is the most common of them. Peroneal nerve compression most commonly occurs at or around the head of the fibula, but can also occur in the lower leg, ankle, or foot. Neurophysiological and neuroimaging methods are effective in diagnosing peroneal nerve compression and determining the type of damage. The first line of therapy is lifestyle modification, avoidance of compressive postures, ankle joint orthotics, treatment of knee joint instability when detected, kinesiotherapy. An important role in the correction of symptoms is played using anticholinesterase drugs, the effectiveness of which in diseases of peripheral nervous system has been shown in a number of domestic studies. If conservative treatment fails, surgical treatment is recommended. The diagnosis of peroneal neuropathy is associated with a good prognosis and most patients experience complete recovery of nerve function.

Immune checkpoint inhibitor-induced myocarditis with myasthenia gravis overlap syndrome: A case report and literature review

The therapeutic value of immune checkpoint inhibitors (ICIs) in a variety of tumors has been found and recognized, and although ICIs have improved the prognosis of many patients with advanced tumors, these drugs sometimes cause immune-related adverse events (irAEs). We report a 67-year-old woman with advanced rectal endocrine tumor. Ten days after receiving two cycles of treatment with camrelizumab combined with http://www.baidu.com/link?url=shAWG4LYTwwBcZAEb6pLb6DkDndJR2tUgOfFiWAkOf0hS-_sj2jjSLBwYaxSiHY3r6yPj31Lp2DCP-7q3w7ho5HIV46V4fbIShFyUY7Cbka sorafenib, the patient suddenly suffered from chest tightness, shortness of breath and progressive aggravation of limb weakness, the high-sensitivity cardiac troponin T (hs-cTnT) was elevated to 3015pg/mL and N-terminal pro-B-type natriuretic peptide (NT-proBNP) up to 5671pg/mL, and creatine kinase (CK) was 1419U/L. The patient was diagnosed as immune checkpoint inhibitor-induced myocarditis with myasthenia gravis overlap syndrome. The patient was transferred to the intensive care unit (ICU) in time and given oxygen inhalation, glucocorticoids, immunoglobulin and anticholinesterase drugs, and other related treatments. After 2 weeks, the symptoms of myasthenia gravis (MG) were relieved, and the level of myocardial injury markers decreased significantly, but it was still at a high level. The patient's family refused further treatment, and the patient died soon after. In this paper, Through the report and follow-up analysis of this case, this paper recognizes that the early correct understanding and evaluation of this fulminant and fatal irAEs and the reasonable treatment of patients are very important for the prognosis of patients.

Exploring facile synthesis and cholinesterase inhibiting potential of heteroaryl substituted imidazole derivatives for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder and cholinesterase (ChE) enzymes are considered as crucial targets for the treatment of AD. Herein, a series of heteroaryl substituted imidazole derivatives (5a-5x) was prepared using amino acid catalyzed, one-pot facile synthetic approach. In this context, the catalytic potentials of different amino acids were investigated and 15 mol% of glutamic acid was identified as the most suitable catalyst to obtain the target products in good yields up to 90 %. These structurally exciting heterocyclic hybrids were screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. This series displayed moderate to excellent inhibitory potential against AChE with IC50 values > 25 µM and the most active compound was 3-(4-(1-(3,5-dimethylphenyl)-4,5-diphenyl-1H-imidazol-2-yl)-1-phenyl-1H-pyrazol-3-yl)–2H-chromen-2-one (5x) with IC50 value of 25.83 ± 0.25 µM.This inhibitory potential was attributed to hydrophobicity as the major contributory factor. The most potent compound against BChE was 1,3-diphenyl-4-(1,4,5-triphenyl-1H-imidazol-2-yl)-1H-pyrazole (5a) with IC50 value of 0.35 ± 0.02 µM followed by other potent compounds 5p, 5 m, 5x, 5b, 5c, 5e and 5f with IC50 values < 10 µM. SAR studies further revealed that coumarinyl moiety at R1 position in the imidazolylpyrazole skeleton significantly improved the overall cholinesterase inhibitory potential. However, a simple phenyl ring attached at this R1 site was highly effective and selective for BChE inhibition (5a) over AChE. Docking data also demonstrated the interaction of 5x and AChE with a docking score of 7564 and atomic contact energy (ACE) value of –291.90 kcal/mol whereas docking score for 5a against BChE was 7096 with ACE value of –332.95 kcal/mol. The results altogether suggest further investigations of the heteroaryl substituted imidazole core skeleton in search of potential leads towards designing of new anti-cholinesterase drugs for the treatment of AD.

New Multifunctional Agents for Potential Alzheimer's Disease Treatment Based on Tacrine Conjugates with 2-Arylhydrazinylidene-1,3-Diketones.

Alzheimer's disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC50 0.24-0.34 µM) and butyrylcholinesterase (BChE, IC50 0.036-0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu2+, Fe2+, and Zn2+, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds 6 and 7 also showed Fe3+ reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development.

Comparison between the Effects of Combination of Atropine plus Glycopyrrolate with Atropine alone on Heart Rate for the Reversal of Muscle Relaxant after General Anesthesia

Background: A muscle relaxant is an integral component of general anesthesia. Anticholinesterase drugs employed as their antagonist are associated with certain untoward effects. To counter these undesirable effects, anticholinergic agents, atropine, and glycopyrrolate are often used. Objectives: To compare and quantify the mean change in heart rate in patients receiving atropine (0.5 mg) alone, glycopyrrolate (0.5 mg) alone, and atropine (0.25 mg) plus glycopyrrolate (0.25 mg) after muscle relaxant reversal with neostigmine. Study Design: Randomized controlled trial Place and Duration of Study: Department of Anesthesiology and General Surgery Operation Theatre, Nishtar Medical University Multan from 1st January 2021 to 30th June 2021. Methodology: Ninety patients fulfilling inclusion and exclusion criteria undergoing elective cholecystectomy or ventral hernia repair under general anesthesia were included in this study. Group A (n= 30) received Atropine 0.5mg IV, Group G (n=30) received Glycopyrrolate 0.5mg IV while Group A+G (n=30) received atropine 0.25mg plus glycopyrrolate 0.25mg. Data regarding patients’ age, gender, ASA status, type of procedure and operation time, detailed clinical history, and laboratory investigations were taken for all patients. Heart rate of patients before muscle relaxant reversal and after 3 minutes of reversal was noted and heart rate change was calculated. Results: Mean change in heart rate in group A+G was 9.06±3.55 beats/min, 18.53±9.61 beats/min in group A and 17.26±6.20 beats/min in group G. This difference was statistically significant with a p-value &lt;0.0001. Conclusion: Atropine and glycopyrrolate combination is more effective than atropine or glycopyrrolate alone in preventing the heart rate variability associated with reversal of neuromuscular blockers using neostigmine. Keywords: tropine, Glycopyrrolate, Heart rate.