Design, synthesis, biological evaluation, and molecular modeling simulations of new phthalazine-1,4-dione derivatives as anti-Alzheimer's agents.

The development of targeted phthalazine-1,4-dione acetylcholinesterase (AChE) inhibitors for treating Alzheimer's disease involved the synthesis of 32 compounds via a multistage process. Various analytical techniques confirmed the compounds' identities. Thirteen compounds were found to inhibit AChE by more than 50% without affecting butyrylcholinesterase (BChE). Among these, three compounds, 8m, 8n, and 8p, exhibited extraordinary activity similar to donepezil, a reference AChE inhibitor. During enzyme kinetic studies, compound 8n, displaying the highest AChE inhibitory activity, underwent evaluation at three concentrations (2 × IC50, IC50, and IC50/2). Lineweaver-Burk plots indicated mixed inhibition activity for compound 8n against AChE, suggesting a combination of competitive and noncompetitive characteristics. Additionally, effective derivatives 8m, 8n, and 8p exhibited high blood-brain barrier (BBB) permeability in in vitro parallel artificial membrane permeability assay tests. Molecular docking studies revealed that these compounds bind to the enzyme's active site residues in a position similar to donepezil. Molecular dynamic simulations confirmed the stability of the protein-ligand system, and the chemical reactivity characteristics of the compounds were investigated using density functional theory. The compounds' wide energy gaps suggest stability and therapeutic potential. This research represents a significant step toward finding a potential cure for Alzheimer's disease. However, further research and testing are required to determine the compounds' safety and efficacy. The unique structure of phthalazine derivatives makes them suitable for various biological activities, and these compounds show promise for developing effective drugs for treating Alzheimer's disease. Overall, the development of these targeted compounds is a crucial advancement in the search for an effective treatment for Alzheimer's disease.

Target isolation of diverse sesquiterpenoid from the stems of Daphne genkwa based on molecular networking.

Guiding by LC-MS/MS analysis and the Global Natural Products Social (GNPS) Molecular Networking, three undescribed sesquiterpenoids, stedapgens A-C, and two known analogues were discovered in the barks of Daphne genkwa Sieb. et Zucc. The structures were determined by analysis of their spectroscopic data and quantum-chemical calculations. All the isolated novel compounds were tested for their acetylcholinesterase inhibitory activities with IC50 = 0.754 ± 0.059, 0.696 ± 0.026, and 0.337 ± 0.023 µg/ml. Among them, stedapgen A displayed promising inhibitory activities against AChE, and the binding sites were predicted by molecular docking.

Cholinergic signaling at the body wall neuromuscular junction distally inhibits feeding behavior in Caenorhabditis elegans.

Complex biological functions within organisms are frequently orchestrated by systemic communication between tissues. In the model organism Caenorhabditis elegans, the pharyngeal and body wall neuromuscular junctions are two discrete structures that control feeding and locomotion, respectively. Separate, the well-defined neuromuscular circuits control these distinct tissues. Nonetheless, the emergent behaviors, feeding and locomotion, are coordinated to guarantee the efficiency of food intake. Here, we show that pharmacological hyperactivation of cholinergic transmission at the body wall muscle reduces the rate of pumping behavior. This was evidenced by a systematic screening of the effect of the cholinesterase inhibitor aldicarb on the rate of pharyngeal pumping on food in mutant worms. The screening revealed that the key determinants of the inhibitory effect of aldicarb on pharyngeal pumping are located at the body wall neuromuscular junction. In fact, the selective stimulation of the body wall muscle receptors with the agonist levamisole inhibited pumping in a lev-1-dependent fashion. Interestingly, this response was independent of unc-38, an alpha subunit of the nicotinic receptor classically expressed with lev-1 at the body wall muscle. This implies an uncharacterized lev-1-containing receptor underpins this effect. Overall, our results reveal that body wall cholinergic transmission not only controls locomotion but simultaneously inhibits feeding behavior.

Acetylcholinesterase inhibition protects against trastuzumab-induced cardiotoxicity through reducing multiple programmed cell death pathways.

BACKGROUND: Trastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases. However, it remains unknown whether donepezil exerts anti-cardiotoxic effects in rats with TIC. We hypothesized that donepezil reduces mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death, leading to improved left ventricular (LV) function in rats with TIC. METHODS: Male Wistar rats were randomly assigned to be Control or Trz groups (Trz 4 mg/kg/day, 7 days, I.P.). Rats in Trz groups were assigned to be co-treated with either drinking water (Trz group) or donepezil 5 mg/kg/day (Trz + DPZ group) via oral gavage for 7 days. Cardiac function, heart rate variability (HRV), and biochemical parameters were evaluated. RESULTS: Trz-treated rats had impaired LV function, HRV, mitochondrial function, and increased inflammation and oxidative stress, leading to apoptosis, ferroptosis, and pyroptosis. Donepezil co-treatment effectively decreased those adverse effects of TIC, resulting in improved LV function. An in vitro study revealed that the cytoprotective effects of donepezil were abolished by a muscarinic acetylcholine receptor (mAChR) antagonist. CONCLUSIONS: Donepezil exerted cardioprotection against TIC via attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, leading to improved LV function through mAChR activation. This suggests that donepezil could be a novel intervention strategy in TIC.

Design, synthesis, and biological evaluation of novel N-Benzyl piperidine derivatives as potent HDAC/AChE inhibitors for Alzheimer's disease.

The multitarget-directed ligands approach represents a potential strategy to provide effective treatments for Alzheimer's disease (AD) given its multifactorial pathology. Herein, a series of N-benzyl piperidine derivatives were designed, synthesized, and biologically characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Among the compounds tested, d5 and d10 exhibited dual enzyme inhibitions (d5: HDACIC50 = 0.17 µM, AChEIC50 = 6.89 µM, d10: HDACIC50 = 0.45 µM, AChEIC50 = 3.22 µM), and both compounds showed activities on scavenging free radical, metal chelating, and inhibiting Aß aggregations. More importantly, both compounds exhibited promising neuroprotective activities in PC-12 cells and good AChE selectivity. Collectively, the multifunctional profiles of compound d5 and d10 encourage further optimization and exploration to develop more potent analogues as potential treatments for AD.

An educational intervention to reduce the incidence of postoperative residual curarisation: a cluster randomised crossover trial in patients undergoing general anaesthesia.

BACKGROUND: The incidence of postoperative residual curarisation remains unacceptably high. We assessed whether an educational intervention on perioperative neuromuscular block management can reduce it. METHODS: In this multicentre, cluster randomised crossover trial, centres were allocated to receive an educational intervention either in a first or a second period. The educational intervention consisted of a lecture about neuromuscular management key points, including quantitative neuromuscular monitoring and use of reversal agents. The lecture was streamed to allow repetition. Additionally, memory cards were distributed in each operating theatre. The primary outcome was postoperative residual curarisation in the PACU. Secondary outcomes were frequency of quantitative neuromuscular monitoring, use of reversal agents, and incidence of postoperative pulmonary complications during hospital stay. Measurements were performed before randomisation and after the first and the second period. The effect of the educational intervention was estimated using multivariable mixed effects logistic regression models. RESULTS: We included 2314 subjects in 34 Spanish centres. Postoperative residual curarisation incidence was not affected by the educational intervention (odds ratio [OR] 0.90 [95% confidence interval {CI}: 0.51-1.58]; P=0.717 and 1.30 [0.73-2.30]; P=0.371] for first and second time-period interaction). The educational intervention increased the quantitative neuromuscular monitor usage (OR 2.04 [95% CI: 1.31-3.19]; P=0.002), the use of reversal agents was unchanged (OR 0.79 [95% CI: 0.50-1.26]; P=0.322), and the incidence of postoperative pulmonary complications decreased (OR 0.19 [95% CI: 0.10-0.35]; P<0.001). CONCLUSIONS: An educational intervention on perioperative neuromuscular block management did not reduce the incidence of postoperative residual curarisation nor increase reversal, despite increased quantitative neuromuscular monitoring. Sugammadex reversal was associated with reduced postoperative residual curarisation. The educational intervention was associated with a decrease in postoperative pulmonary complications. CLINICAL TRIAL REGISTRATION: NCT03128151.

Design, synthesis, and evaluation of hydrazones as dual inhibitors of ryanodine receptors and acetylcholinesterases for Alzheimer's disease.

Alzheimer's disease (AD) implicates neuronal loss, plaque and neurofibrillary tangle formation, and disturbed neuronal Ca2+ homeostasis, which leads to severe dementia, memory loss, as well as thinking and behavioral perturbations that could ultimately lead to death. Calcium dysregulation and low acetylcholine levels are two main mechanisms implicated in Alzheimer's disease progression. Simultaneous inhibition of calcium oscillations (store overload-induced Ca2+ release [SOICR]) and acetylcholinesterase (AChE) by a single molecule may bring a new breath of hope for AD treatment. Here, we described some dantrolene derivatives as dual inhibitors of the ryanodine receptor and AChE. Two series of acylhydrazone/sulfonylhydrazone derivatives with aromaticgroup were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit SOICR and AChE in vitro, using dantrolene and donepezil as positive controls. Compound 22a exhibited excellent and balanced inhibitory potency against SOICR (inhibition (%) = 90.1, IC50 = 0.162 µM) and AChE (inhibition (%) = 93.5, IC50 = 0.372 µM). Docking simulations showed that several preferred compounds could bind to the active sites of both the proteins, further validating the rationality of the design strategy. Potential therapeutic effects in AD were evaluated using the Barnes maze and Morris water maze tests, which demonstrated that compound 22a significantly improved memory and cognitive behavior in AD model mice. Moreover, it was also found that compound 22a could enhance synaptic strength by measuring hippocampal long-term potentiation (LTP) in brain slices. These results suggested that the introduction of a sulfonyl-hydrazone scaffold and aromatic substitution to dantrolene derivatives provided a useful template for the development of potential chemical entities against AD.

(±)-Yanhusuomide A, a pair of ornithine-fused benzylisoquinoline enantiomers from Corydalis yanhusuo.

(±)-Yanhusuomide A (1), a novel enantiomeric pair of ornithine-fused benzylisoquinoline, were characterized from the dried tubers of Corydalis yanhusuo, along with a biogenetically related intermediate oblongine (2). Yanhusuomide A features an unprecedented skeleton based on a benzylisoquinoline coupled with an ornithine derivative to form a rare 5,6-dihydro-4H-pyrido[3,4,5-de]quinazoline motif. Plausible biosynthetic pathway of 1 was proposed, and (±)-yanhusuomide A (1) presented potential inhibitory bioactivity against acetylcholinesterase (AChE) with IC50 = 14.07 ± 2.38 µM. The simulation of molecular docking displayed that 1 generated strong interaction with Asp-74 and Trp-86 residues of AChE through attractive charge of the quaternary nitrogen.

Pathology and prevention of brain microvascular and neuronal dysfunction induced by a high-fructose diet in rats.

A high-fructose diet causes metabolic abnormalities in rats, and the cluster of complications points to microvascular and neuronal disorders of the brain. The aim of this study was to evaluate i) the involvement of microvascular disorders and neuronal plasticity in the deleterious effects of a high-fructose diet on the rat brain and ii) a comparative assessment of the effectiveness of Phytocollection therapy (with antidiabetic, antioxidant, and acetylcholinesterase inhibitory activities) compared to Galantamine as first-line therapy for dementia and Diabeton as first-line therapy for hyperglycemia. The calcium adenosine triphosphate non-injection histoangiological method was used to assess capillary network diameter and density. A high-fructose diet resulted in a significant decrease in the diameter and density of the capillary bed, and pharmacological manipulations had a modulatory effect on microcirculatory adaptive mechanisms. In vivo single-unit extracellular recording was used to investigate short-term plasticity in the medial prefrontal cortex. Differences in the parameters of spike background activity and expression of excitatory and inhibitory responses of cortical neurons have been discovered, allowing for flexibility and neuronal function stabilization in pathology and pharmacological prevention. Integration of the coupling mechanism between microvascular function and neuronal spike activity could delay the progressive decline in cognitive function in rats fed a high fructose diet.

Design, Synthesis, and Biological Evaluation of Novel Indanone Derivatives as Cholinesterase Inhibitors for Potential Use in Alzheimer's Disease.

Indanone derivatives containing meta/para-substituted aminopropoxy benzyl/benzylidene moieties were designed based on the structures of donepezil and ebselen analogs as the cholinesterase inhibitors. The designed compounds were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were measured. Inhibitory potencies (IC50 values) for the synthesized compounds ranged from 0.12 to 11.92 µM and 0.04 to 24.36 µM against AChE and BChE, respectively. Compound 5 c showed the highest AChE inhibitory potency with IC50 value of 0.12 µM, whereas the highest BChE inhibition was achieved by structure 7 b (IC50 =0.04 µM). Structure-activity relationship (SAR) analysis revealed that there is no significant difference between meta and para-substituted derivatives in AChE and BChE inhibition. However, the most potent AChE inhibitor 5 c belongs to meta-substituted compounds, while the most active BChE inhibitor is para-substituted derivative 7 b. The order of enzyme inhibition potency based on the substituted amine group is dimethyl amine>piperidine>morpholine. Compounds containing C=C linkage are more potent AChE inhibitors than the corresponding saturated structures. Molecular docking studies indicated that 5 c interacts with AChE in a very similar way to that observed experimentally for donepezil. The introduced indanone-aminopropoxy benzylidenes could be used in drug-discovery against Alzheimer's disease.

Design, Synthesis, Molecular Docking, and Molecular Dynamics Simulation Studies of Novel 3-Hydroxypyridine-4-one Derivatives as Potential Acetylcholinesterase Inhibitors.

Researchers have focused on inhibiting acetylcholinesterase for Alzheimer's disease treatment. In this study, some novel AChE inhibitors were synthesized using hydroxypyridin-4-one plus benzylpiperidine scaffolds which were evaluated using Ellman's method. Accordingly, ((1-(4-methoxyphenethyl)piperidin-4-yl)amino)methyl)-5-hydroxy-1-methylpyridin-4(1H)-one (VIId ) showed weaker but promising AChE inhibition compared to donepezil (IC50 =143.090 nM). The average RMSD values of VIId was found to be 2.25 indicated less structural changes in the active site residues. The phenyl group of the phenyl-ethyl-N-piperidine moiety of VIId formed hydrophobic interactions with Trp285 and Tyr340. There was a π-cation interaction between nitrogen atom of piperidine ring and Phe294. Another π-cation interaction was found between type 2 amine of linker and Trp85. Piperidine ring interacted with Tyr336, Tyr123, and Phe337 through hydrophobic interactions. Indeed, the VIId was predicted to be absorbed across the gastrointestinal tract, though it may be pumped out by P-gp. Indeed, VIId can permeate through the blood brain barrier. MD simulation studies revealed that benzyloxy moiety plays a role similar to benzylpiperidine moiety of donepezil in binding to the active site residues. Also, carbonyl group functioned similar to indanone ketone group. Overall; further research on VIId may lead to introduction of a novel class of AChE inhibitors.

Acetylcholinesterase Inhibitory Activity of Modified Lupane, Oleanane, and Ursane A-seco-Triterpenoids.

A series of new lupane, ursane, and oleanane type triterpenic A-seco-derivatives containing bromo-, azido-, alkyne-, 1H-tetrazol-5-yl-, 5-methyloxazol-2-yl-, N-(4-(4-methylpiperazin-1-yl)but-2-yn-1-yl), and a carbonyl group at C2, C24, C28, C30 positions has been synthesized. The bioactivity was evaluated by Ellman's method, and the results showed that most of the compounds displayed moderate acetylcholinesterase inhibitory activities in vitro. Among them, A-seco-derivatives of 28-oxo-allobetuline and betulinic acid with bromo- and azido-groups exhibited the most potent inhibitory activity against AChE. Extra experiments showed methyl 2-cyano-3,4-seco-dibromo- and 2-cyano-3,4-seco-diazido-derivatives of betulinic acid as mixed-type inhibitors, with Ki values as low as Ki =0.18 µM and Ki =0.21 µM, respectively.

Effect of neuromuscular reversal with neostigmine/glycopyrrolate versus sugammadex on postoperative ileus following colorectal surgery.

BACKGROUND: Postoperative ileus (POI) is a common complication following colorectal surgery and is mediated in part by the cholinergic anti-inflammatory pathway (CAIP). Neostigmine (acetylcholinesterase inhibitor), co-administered with glycopyrrolate, is frequently given for neuromuscular reversal before tracheal extubation and modulates the CAIP. An alternative reversal agent, sugammadex (selective rocuronium or vecuronium binder), acts independently from the CAIP. The aim of our study was to assess the impact of neuromuscular reversal agents used during anaesthesia on gastrointestinal recovery. METHODS: Three hundred thirty-five patients undergoing elective colorectal surgery at the Royal Adelaide Hospital between January 2019 and December 2021 were retrospectively included. The primary outcome was GI-2, a validated composite measure of time to diet tolerance and passage of stool. Demographics, 30-day complications and length of stay were collected. Univariate and multivariate analyses were performed. RESULTS: Two hundred twenty-four (66.9%) patients (129 [57.6%] males and 95 [42.4%] females, median age 64 [19-90] years) received neostigmine/glycopyrrolate and 111 (33.1%) received sugammadex (62 [55.9%] males and 49 [44.1%] females, median age 67 [18-94] years). Sugammadex patients achieved GI-2 sooner after surgery (median 3 (0-10) vs. 3 (0-12) days, p = 0.036), and reduced time to first stool (median 2 (0-10) vs. 3 (0-12) days, p = 0.035). Rates of POI, complications and length of stay were similar. On univariate analysis, POI was associated with smoking history, previous abdominal surgery, colostomy formation, increased opioid use and postoperative hypokalaemia (p < 0.05). POI was associated with increased complications, including anastomotic leak and prolonged hospital stay (p < 0.001). On multivariate analysis, neostigmine, bowel anastomoses and increased postoperative opioid use (p < 0.05) remained predictive of time to GI-2. CONCLUSIONS: Patients who received sugammadex had a reduced time to achieving first stool and GI-2. Neostigmine use, bowel anastomoses and postoperative opioid use were associated with delayed time to achieving GI-2.

Acetylcholinesterase inhibition studies of alkaloid components from Crinum asiaticum var. sinicum: in vitro assessments by molecular docking and molecular dynamics simulations.

Alkaloids are among the most important and best-known secondary metabolites as sources of new drugs from medicinal plants and marine organisms. A phytochemical investigation of the whole plant of Crinum asiaticum var. sinicum resulted in the isolation of seven alkaloids (1-7), including one new dimeric compound, bis-(-)-8-demethylmaritidine (1). Their structures were elucidated using NMR and HR-ESI-MS. The absolute configuration of new compound 1 was established by circular dichroism spectroscopy. All isolated compounds were evaluated for their inhibitory effects on acetylcholinesterase (AChE) activity in vitro. Among them, compound 1 exhibited the most potent AChE inhibition. Moreover, molecular docking and molecular dynamics simulations were carried out for the most active compound to investigate their binding interactions and dynamics behavior of the AChE protein-ligand complex. Therefore, compound 1 may be a potential candidate for effectively treating Alzheimer's disease.

Design, synthesis, in vitro, and in vivo evaluation of novel phthalazinone-based derivatives as promising acetylcholinesterase inhibitors for treatment of Alzheimer's disease.

Twenty novel phthalazinone-based compounds were designed as acetylcholinesterase (hAChE) inhibitors. Compounds 7e and 17c demonstrated comparable or superior activity compared to donepezil, respectively, in in vitro enzyme assay. Moreover, both compounds 7e and 17c possess minimal toxicity on hepatic and neuroblastoma cell lines. Besides, it was proved that compounds 7e and 17c have percentage alternations and a transfer latency time comparable to donepezil and can alleviate the cognitive impairment caused by the scopolamine-induced model in mice. The kinetic analysis for compound 17c suggested this compound as a mixed-type inhibitor that could bind to both the peripheral (PAS) and the catalytic site (CAS) of the hAChE enzyme. The synthesized molecules were subjected to in silico analyses, including molecular docking studies, and the outcomes were consistent with the in vitro findings.

Inhibition of Acetylcholinesterase by Novel Lupinine Derivatives.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment due in part to a severe loss of cholinergic neurons in specific brain areas. AD is the most common type of dementia in the aging population. Although several acetylcholinesterase (AChE) inhibitors are currently available, their performance sometimes yields unexpected results. Thus, research is ongoing to find potentially therapeutic AChE inhibitory agents, both from natural and synthetic sources. Here, we synthesized 13 new lupinine triazole derivatives and evaluated them, along with 50 commercial lupinine-based esters of different carboxylic acids, for AChE inhibitory activity. The triazole derivative 15 [1S,9aR)-1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-2H-quinolizine)] exhibited the most potent AChE inhibitory activity among all 63 lupinine derivatives, and kinetic analysis demonstrated that compound 15 was a mixed-type AChE inhibitor. Molecular docking studies were performed to visualize interaction between this triazole derivative and AChE. In addition, a structure-activity relationship (SAR) model developed using linear discriminant analysis (LDA) of 11 SwissADME descriptors from the 50 lupinine esters revealed 5 key physicochemical features that allowed us to distinguish active versus non-active compounds. Thus, this SAR model could be applied for design of more potent lupinine ester-based AChE inhibitors.

Enhanced parasympathetic cholinergic activity with galantamine inhibited lipid-induced oxidative stress in obese African Americans.

BACKGROUND: African Americans (AAs) are disproportionately affected by cardiovascular disease (CVD), they are 20% more likely to die from CVD than whites, chronic exposure to inflammation and oxidative stress contributes to CVD. In previous studies, enhancing parasympathetic cholinergic activity has been shown to decrease inflammation. Considering that AAs have decreased parasympathetic activity compared to whites, we hypothesize that stimulating it with a central acetylcholinesterase (AChE) inhibitor, galantamine, would prevent lipid-induced oxidative stress. OBJECTIVE: To test the hypothesis that acute dose of galantamine, an AChE inhibitor, decreases lipid-induced oxidative stress in obese AAs. METHODS: Proof-of-concept, double-blind, randomized, placebo-controlled, crossover study that tested the effect of a single dose of 16 mg of galantamine versus placebo on lipid-induced oxidative stress in obese AAs. Subjects were studied on two separate days, one week apart. In each study day, 16 mg or matching placebo was administered before 20% intralipids infusion at doses of 0.8 mL/m2/min with heparin at doses of 200 U/h for 4 h. Outcomes were assessed at baseline, 2 and 4 h during the infusion. MAIN OUTCOME MEASURES: Changes in F2-isoprostane (F2-IsoPs), marker of oxidative stress, measured in peripheral blood mononuclear cells (PBMC) and in plasma at baseline, 2, and 4-h post-lipid infusion. Secondary outcomes include changes in inflammatory cytokines (IL-6, TNF alpha). RESULTS: A total of 32 obese AA women were screened and fourteen completed the study (age 37.8 ± 10.70 years old, BMI 38.7 ± 3.40 kg/m2). Compared to placebo, 16 mg of galantamine significantly inhibited the increase in F2-IsoPs in PBMC (0.007 ± 0.008 vs. - 0.002 ± 0.006 ng/sample, P = 0.016), and plasma (0.01 ± 0.02 vs. - 0.003 ± 0.01 ng/mL, P = 0.023). Galantamine also decreased IL-6 (11.4 ± 18.45 vs. 7.7 ± 15.10 pg/mL, P = 0.021) and TNFα levels (18.6 ± 16.33 vs. 12.9 ± 6.16 pg/mL, P = 0.021, 4-h post lipid infusion) compared with placebo. These changes were associated with an increased plasma acetylcholine levels induced by galantamine (50.5 ± 10.49 vs. 43.6 ± 13.38 during placebo pg/uL, P = 0.025). CONCLUSIONS: In this pilot, proof-of-concept study, enhancing parasympathetic nervous system (PNS) cholinergic activity with galantamine inhibited lipid-induced oxidative stress and inflammation induced by lipid infusion in obese AAs. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02365285.

Personalised treatment for cognitive impairment in dementia: development and validation of an artificial intelligence model.

BACKGROUND: Donepezil, galantamine, rivastigmine and memantine are potentially effective interventions for cognitive impairment in dementia, but the use of these drugs has not been personalised to individual patients yet. We examined whether artificial intelligence-based recommendations can identify the best treatment using routinely collected patient-level information. METHODS: Six thousand eight hundred four patients aged 59-102 years with a diagnosis of dementia from two National Health Service (NHS) Foundation Trusts in the UK were used for model training/internal validation and external validation, respectively. A personalised prescription model based on the Recurrent Neural Network machine learning architecture was developed to predict the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores post-drug initiation. The drug that resulted in the smallest decline in cognitive scores between prescription and the next visit was selected as the treatment of choice. Change of cognitive scores up to 2 years after treatment initiation was compared for model evaluation. RESULTS: Overall, 1343 patients with MMSE scores were identified for internal validation and 285 [21.22%] took the drug recommended. After 2 years, the reduction of mean [standard deviation] MMSE score in this group was significantly smaller than the remaining 1058 [78.78%] patients (0.60 [0.26] vs 2.80 [0.28]; P = 0.02). In the external validation cohort (N = 1772), 222 [12.53%] patients took the drug recommended and reported a smaller MMSE reduction compared to the 1550 [87.47%] patients who did not (1.01 [0.49] vs 4.23 [0.60]; P = 0.01). A similar performance gap was seen when testing the model on patients prescribed with AChEIs only. CONCLUSIONS: It was possible to identify the most effective drug for the real-world treatment of cognitive impairment in dementia at an individual patient level. Routine care patients whose prescribed medications were the best fit according to the model had better cognitive performance after 2 years.

Divulging the anti-acetylcholinesterase activity of Colletotrichum lentis strain KU1 extract as sustainable AChE active site inhibitors.

Alzheimer's disease (AD), also called senile dementia is a neurodegenerative disease seen commonly in the elderly and is characterised by the formation of ß-amyloid plaques and neurofibrillary tangles (NFT). Though a complete understanding of the disease is lacking, recent studies showed the role of the enzyme acetylcholinesterase (AChE) in pathogenesis. Finding new lead compounds from natural sources has always been a quest for researchers. Endophytic fungi are a set of microbes that reside within plants without causing any harm. This study focuses on screening endophytes for the production of active acetylcholinesterase inhibitors. Five endophytic fungi were isolated from Catharanthus roseus and screened for AChE inhibitory activity. Three isolates were found to inhibit AChE inhibitory activity and were distinguished based on molecular and microscopic methods. The mycelial extract was taken for the bioassay-guided column chromatography and TLC was performed on the active fraction. The GC-MS and NMR analysis identified the active compounds in the extract as 9-hexadecen-1-ol and erucamide. Molecular docking studies revealed that the compounds are thermodynamically feasible and have significant glide scores. Computational studies revealed that the hydroxyl group of 9-hexadecen-1-ol forms a hydrogen bond with Ser 293 in the active site of AChE, whereas the active site interactions were predominantly hydrophobic in the case of erucamide and are reflected in AChE inhibition assays.

Design, synthesis and evaluation of 2-(2-oxoethyl)pyrimidine-5-carboxamide derivatives as acetylcholinesterase inhibitors.

A novel series of 2-(2- oxoethyl)pyrimidine-5-carboxamide derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that compound 10q showed the best inhibitory activity against AChE (IC50 = 0.88 ± 0.78 µM), which was better than that of Huperzine-A, and its inhibitory effect on BuChE was weak (IC50 = 10.0 ± 1.30 µM), which indicated that compound 10q was a dominant AChE inhibitor. In addition, the result of molecular docking study displayed that 10q could simultaneously bind to CAS and PAS sites of AChE, which was consistent with the mixed inhibition mode shown by the enzymatic kinetics study of 10q. Furthermore, the molecular properties of the target compounds were predicted online using the molinspiration server and pkCSM, The results exhibited that compound 10q had drug-like properties that satisfied the Lipinski's rule of five. Based on the bioactivity and molecular properties, compound 10q for further development was valuable.