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[Display omitted] Alzheimer's disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated with complex pathophysiology. Presently, the USFDA has approved only four drugs viz. Donepezil, Rivastigmine, Memantine, and Galantamine for the treatment of AD. These drugs exhibit their neuroprotective effects either by inhibiting cholinesterase enzyme (ChE) or N -methyl- d -aspartate (NMDA) receptor. However, the conventional therapy "one target, one molecule" has failed to provide promising therapeutic effects due to the multifactorial nature of AD. This triggered the development of a novel strategy called Multi-Target Directed Ligand (MTDL) which involved designing one molecule that acts on multiple targets simultaneously. The present review discusses the detailed pathology involved in AD and the various MTDL design strategies bearing different heterocycles, in vitro and in vivo activities of the compounds, and their corresponding structure–activity relationships. This knowledge will allow us to identify and design more effective MTDLs for the treatment of AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series bis-acylhydrazones of 2,2′-([1,1′-biphenyl]-4,4′-diylbis(oxy))di(acetohydrazide) (1 – 27) was synthesized. • The structures were confirmed by 1H NMR, 13C NMR, and ESI-MS. • All compounds displayed significant acetylcholinesterase (AChE) and butyrylcholinesterase inhibition. • Molecular docking studies were performed to establish their structure–activity relationship and binding interaction at atomic level. A series of twenty-seven bis (acylhydrazones) were successfully synthesized with high yields through a multistep process, which entailed the esterification of hydroxyl groups, hydrazination with an excess of hydrazine hydrate, and subsequent reactions with various carbonyl moieties (aldehydes). In the final stage of synthesis, different chemical species including aromatic, heterocyclic, and aliphatic compounds were integrated into the framework. The resulting compounds were characterized using several spectroscopic techniques (1H NMR, 13C NMR, and mass spectrometry). Their anticholinesterase activities were assessed in vitro by examining their interactions with two cholinesterase enzymes: acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the synthesized hits, compounds 3, 5, 6, 9 – 12, and 14 exhibited good to moderate inhibition of AChE. Specifically, 10 (IC 50 = 26.3 ± 0.4 μM) and 11 (IC 50 = 28.4 ± 0.5 μM) showed good inhibitory activity against AChE, while 9, 12, 3, and 6 exhibited significant inhibition potential against AChE with IC 50 values ranging from 35.2 ± 1.1 μM to 64.4 ± 0.3 μM. On the other hand, 5 (IC 50 = 22.0 ± 1.1 μM) and 27 (IC 50 = 31.3 ± 1.3 μM) displayed significant, and 19 (IC 50 = 92.6 ± 0.4 μM) showed moderate inhibitory potential for BChE. Notably, 5 and 27 exhibited dual inhibition of AChE and BChE, with greater potency than the standard drug galantamine. The binding patterns of these molecules within the binding cavities of AChE and BChE were anticipated by molecular docking which showed good correlation with our in vitro findings. Further structural optimization of these molecules may yield more potent AChE and BChE inhibitors. [ABSTRACT FROM AUTHOR]

Four series of novel donepezil-tacrine hybrids moiety were designed, synthesized, and evaluated in this study. [Display omitted] • Four series of novel donepezil-tacrine hybrids were designed, synthesized, and evaluated in this study. • The inhibitory activities of all target compounds against AChE were tested and the SARs were analyzed. Meanwhile, the inhibitory activities of the preferred compounds against BuChE were evaluated. • Compound B19 showed low neurotoxicity on the PC12 cell viability at the concentration of 25 μM and protected cells against H 2 O 2 -induced neurotoxicity in a dose-dependent manner. • Compound B19 demonstrated significant ability to protect PC12 cells from H 2 O 2 -induced apoptosis by Annexin V-FITC/PI assay. • Compound B19 could protect PC12 cells from reactive oxygen species (ROS) production. • Compound B19 exhibited satisfactory anti-inflammatory activity on LPS-induced NO production assay. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and deficits in cognitive domains. Low choline levels, oxidative stress, and neuroinflammation are the primary mechanisms implicated in AD progression. Simultaneous inhibition of acetylcholinesterase (AChE) and reactive oxygen species (ROS) production by a single molecule may provide a new breath of hope for AD treatment. Here, we describe donepezil-tacrine hybrids as inhibitors of AChE and ROS. Four series of derivatives with a β-amino alcohol linker were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit AChE and butyrylcholinesterase (BuChE) in vitro , using tacrine (h AChE, IC 50 = 305.78 nM; h BuChE, IC 50 = 56.72 nM) and donepezil (h AChE, IC 50 = 89.32 nM; h BuChE, IC 50 = 9137.16 nM) as positive controls. Compound B19 exhibited an excellent and balanced inhibitory potency against AChE (IC 50 = 30.68 nM) and BuChE (IC 50 = 124.57 nM). The cytotoxicity assays demonstrated that the PC12 cell viability rates of compound B19 (84.37 %) were close to that of tacrine (87.73 %) and donepezil (79.71 %). Potential therapeutic effects in AD were evaluated using the neuroprotective effect of compounds against H 2 O 2 -induced toxicity, and compound B19 (68.77 %) exhibited substantially neuroprotective activity at the concentration of 25 μM, compared with the model group (30.34 %). Furthermore, compound B19 protected PC12 cells from H 2 O 2 -induced apoptosis and ROS production. These properties of compound B19 suggested that it was a multi-functional agent with AChE inhibition, anti-oxidative, anti-inflammatory activities, and low toxicity and that it deserves further investigation as a promising agent for AD treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • Piperazine-2-carboxylic acid derivatives competitive cholinesterase inhibitors. • Piperazinyl carboxylic acid 4c inhibits AChE (Ki = 10.18 ± 1.00 µM; SI ∼ 17.90). • Piperazinyl hydroxamic acid 7b inhibits BChE (Ki = 1.62 ± 0.08 nM, SI = 2186.2). • 4c and 7b are less cyctotoxic than staurosporine. • Flexible assignments, molecular docking, and dynamic simulations results demonstrate similar interactions as that of donepezil, the reference drugs. Development of Multitarget-Directed Ligands (MTDLs) is a promising approach to combat the complex etiologies of Alzheimer's disease (AD). Herein we report the design, synthesis, and characterization of a new series of 1,4-bisbenzylpiperazine-2-carboxylic acid derivatives 3 - 5(a-g), 7a-f , 8a-s , and their piperazine-2-yl-1,3,4-oxadiazole analogs 6a-g. In vitro inhibitory effect against Electrophorus electricus acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) from Equine serum was evaluated using modified Ellman's method, considering donepezil and tacrine as reference drugs. Lineweaver–Burk plot analysis of the results proved competitive inhibition of AChE and BChE with Ki values, in low micromolar range. The free carboxylic acid series 4a-g showed enhanced selectivity for AChE. Hence, 4c, 1,4-bis (4-chlorobenzyl)-piperazinyl-2-carboxylic acid), was the most active member of this series (Ki (AChE) = 10.18 ± 1.00 µ M) with clear selectivity for AChE (SI ∼ 17.90). However, the hydroxamic acids 7a-f and carboxamides 8a-s congeners were more potent and selective inhibitors of BChE (SI ∼ 5.38 – 21862.5). Extraordinarily, 1,4-bis (2-chlorobenzyl)-piperazinyl-2-hydroxamic acid 7b showed promising inhibitory activity against BChE enzyme (Ki = 1.6 ± 0.08 nM, SI = 21862.5), that was significantly superior to that elicited by donepezil (Ki = 12.5 ± 2.6 µ M) and tacrine (Ki = 17.3 ± 2.3 nM). Cytotoxicity assessment of 4c and 7b, on human neuroblastoma (SH-SY5Y) cell lines, revealed lower toxicity than staurosporine and was nearly comparable to that of donepezil. Molecular docking and molecular dynamics simulation afforded unblemished insights into the structure–activity relationships for AChE and BChE inhibition. The results showed stable binding with fair H-bonding, hydrophobic and/or ionic interactions to the catalytic and peripheral anionic sites of the enzymes. In silico predicted ADME and physicochemical properties of conjugates showed good CNS bioavailability and safety parameters. In this regard, compound (7b) might be considered as a promising inhibitor of BChE with an innovative donepezil-based anti-Alzheimer activity. Further assessments of the most potent AChE and BChE inhibitors as potential MTDLs anti-Alzheimer's agents are under investigation with our research group and will be published later. [ABSTRACT FROM AUTHOR]

[Display omitted] • Decasubstituted pillar[5]arenes with terminal amino acid residues were synthesized. • The application of pillar[5]arenes as effective cholinesterae inhibitors was shown. • The toxicity of the pillar[5]arenes was due to the formation of stable aggregates. • Compounds with Gly and l -Ala residues showed a low inhibitory ability against ChE. • Pillar[5]arene containing fragments of l -Phe is the most promising inhibitor of BChE. Cholinesterase inhibitors are a group of medicines that are widely used for the treatment of cognitive impairments accompanying Alzheimer's disease as well as for the treatment of pathological muscle weaknesses syndromes such as myasthenia gravis. The search for novel non-toxic and effective cholinesterase inhibitors for creating neuroprotective and neurotransmitter agents is an urgent interdisciplinary problem. For the first time, the application of water-soluble pillar[5]arenes containing amino acid residues as effective cholinesterase inhibitors was shown. The influence of the nature of aliphatic and aromatic alpha-amino acid residues (glycine, l –alanine, l –phenylalanine and l -tryptophan) on self-assembly, aggregate's stability, cytotoxicity on A549 and LEK cells and cholinesterase inhibition was studied. It was found that the studied compounds with aliphatic amino acid residues showed a low inhibitory ability against cholinesterases. It was established that the pillar[5]arene containing fragments of l -phenylalanine is the most promising inhibitor of butyrylcholinesterase (IC 50 = 0.32 ± 0.01 μM), the pillar[5]arene with l -tryptophan residues is the most promising inhibitor of acetylcholinesterase (IC 50 = 0.32 ± 0.01 μM). This study has shown a possible application of peptidomimetics based on pillar[5]arenes to inhibit cholinesterase, as well as control the binding affinity to a particular enzyme in a structure-dependent manner. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design and discovery of pyrimidine-morpholine hybrids. • In vitro cholinesterase inhibitory potential using Ellman's method. • Compound 5h emerged as a lead candidate against AChE. • Molecular dynamics simulation revealed the stability of biomolecular system. The identification of effective and druggable cholinesterase inhibitors to treat progressive neurodegenerative Alzheimer's disorder remains a continuous drug discovery hunt. In this perspective, the present study investigates the design and discovery of pyrimidine-morpholine hybrids (5a-l) as potent cholinesterase inhibitors. Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction was employed to introduce the structural diversity on the pyrimidine heterocyclic core. A range of commercially available boronic acids was successfully coupled showing a high functional group tolerance. In vitro cholinesterase inhibitory potential using Ellman's method revealed significantly strong potency. Compound 5h bearing a meta -tolyl substituent at 2-position of pyrimidine ring emerged as a lead candidate against AChE with an inhibitory potency of 0.43 ± 0.42 µM, ∼38-fold stronger value than neostigmine (IC 50 = 16.3 ± 1.12 µM). Compound 5h also showed the lead inhibition against BuChE with an IC 50 value of 2.5 ± 0.04 µM. The kinetics analysis of 5h revealed the non-competitive mode of inhibition against AChE whereas computational modelling results of potent leads depicted diverse contacts with the binding site amino acid residues. Molecular dynamics simulations revealed the stability of biomolecular system, while, ADME analysis demonstrated druglikeness behaviour of potent compounds. Overall, the investigated pyrimidine-morpholine scaffold presented a remarkable potential to be developed as efficacious anti-Alzheimer's drugs. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Biphenyl-3-oxo-1,2,4-triazine linked piperazines were designed and synthesized. • Compound 6g significantly inhibited the AChE and showed good CNS permeability. • In vivo studies showed significant improvement in learning and memory. • Biochemical analysis showed potential antioxidant property by compound 6g. Abstract A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC 50 ; 0.2 ± 0.01 μM) compared to standard donepezil (AChE, IC 50 : 0.1 ± 0.002 μM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ± 1.11%) and showed good CNS permeability in PAMPA-BBB assay (P e (exp) , 6.93 ± 0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Series of hydroxylated 2-phenylbenzofuran were synthesized. • Compounds displayed activity against butyrylcholinesterase enzyme. • Importance of number and position of hydroxyl substitution in enzyme activity. • Physicochemical properties of derivatives were characterized. • Docking studies assisted in explaining the structure-activity. Abstract We have designed, synthesized and evaluated a series of hydroxylated 2-phenylbenzofuran derivatives as potential cholinesterase inhibitors. Starting from a series of 2-phenylbenzofurans previously published, in this paper we present a complete synthesis and the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring and highlight the importance of position of hydroxyl groups. Moreover, simultaneous introduction of halogen at position 7 of the benzofuran scaffold resulted in an improved inhibitory activity against the enzyme. To further provide molecular insight and to identify the most probable ligand-binding site of the protein, docking studies were performed for the top-ranked compounds. Docking results revealed conserved ligand-binding residues and supported the role of catalytic site residues in enzyme inhibition. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 26 O-alkylcoumarins were synthesized and tested at 100 µM for their in vitro inhibitory potential against cholinesterases. • 12 of them exerted a potent and selective inhibition against BChE. • None of them possessed any potential to inhibit AChE. • MetaCore/MetaDrug analysis and docking simulations were applied the active compounds. Abstract Coumarins of synthetic or natural origins are an important chemical class exerting diverse pharmacological activities. In the present study, 26 novel O-alkylcoumarin derivatives were synthesized and have been tested at 100 µM for their in vitro inhibitory potential against acetylcholinesterase (AChE) and butyrlcholinesterase (BChE) targets which are the key enzymes playing role in the pathogenesis of Alzheimer's disease. Among the tested coumarins, none of them could inhibit AChE, whereas 12 of them exerted a marked and selective inhibition against BChE as compared to the reference (galanthamine, IC 50 = 46.58 ± 0.91 µM). In fact, 10 of the active coumarins showed higher inhibition (IC 50 = 7.01 ± 0.28 µM – 43.31 ± 3.63 µM) than that of galanthamine. The most active ones were revealed to be 7-styryloxycoumarin (IC 50 = 7.01 ± 0.28 µM) and 7-isopentenyloxy-4-methylcoumarin (IC 50 = 8.18 ± 0.74 µM). In addition to the in vitro tests, MetaCore/MetaDrug binary QSAR models and docking simulations were applied to evaluate the active compounds by ligand-based and target-driven approaches. The predicted pharmacokinetic profiles of the compounds suggested that the compounds reveal lipophilic character and permeate blood brain barrier (BBB) and the ADME models predict higher human serum protein binding percentages (>50%) for the compounds. The calculated docking scores indicated that the coumarins showing remarkable BChE inhibition possessed favorable free binding energies in interacting with the ligand-binding domain of the target. Therefore, our results disclose that O-alkylcoumarins are promising selective inhibitors of cholinesterase enzymes, particularly BChE in our case, which definitely deserve further studies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • One-pot four component methodology was developed under Cu/Zn dual catalysis. • A diverse range of thiazolidin-2-imines was prepared in excellent yields. • Good functional group tolerance and broad substrate scope were explored. • Potent inhibitors (5b , 5i , 5s , 5t) of acetylcholinesterase were identified. Abstract An efficient one-pot four-component strategy involving aldehydes, amines, alkynes and isothiocyanates has been developed to access a novel series of thiazolidine-2-imines (5a-x). This process operates under the action of a cooperative catalysis composed of Cu(I) and Zn(II) delivering the desired five-membered heterocyclic compounds in good to excellent yields. Notably, this transformation avoids the use of pre-formed imines or propargylamines and proceeds via an intramolecular 5- exo-dig hydrothiolation reaction of the in situ formed propargyl thiourea. Furthermore, the biological application of these motifs was demonstrated in terms of their strong acetylcholinesterase (AChE) inhibitory activity where compound 5s was identified as the lead AChE inhibitor with an IC 50 value of 0.0023 ± 0.0002 μM, 88-folds stronger inhibition than standard drug (neostigmine methyl sulphate; IC 50 = 0.203 ± 0.004 μM). Molecular docking analysis reinforced the in vitro biological activity results revealing the formation of several useful interactions of the potent lead with amino acid residues in the active site of the enzyme. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 16 new Schiff base derivatives were synthesized. • Synthesized compounds were evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes inhibitory activities. • Compounds 3g and 3h were found as the most potent derivatives against AChE and MAO-B enzymes, respectively. • A good ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) profile was predicted for all synthesized compounds. • Molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. Abstract In the current work, Schiff base derivatives of antipyrine were synthesized. The chemical characterization of the compounds was confirmed using IR, 1H NMR, 13C NMR and mass spectroscopies. The inhibitory potency of synthesized compounds was investigated towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes. Some of the compounds displayed significant inhibitory activity against AChE and MAO-B enzymes, respectively. According to AChE enzyme inhibition assay, compounds 3e and 3g were found as the most potent derivatives with IC 50 values of 0.285 µM and 0.057 µM, respectively. Also, compounds 3a (IC 50 = 0.114 µM), 3h (IC 50 = 0.049 µM), and 3i (IC 50 = 0.054 µM) were the most active derivatives against MAO-B enzyme activity. So as to understand inhibition type, enzyme kinetics studies were carried out. Furthermore, molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) permeability predictions were applied to estimate pharmacokinetic profiles of synthesized compounds. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • In this report, a series of eighteen pyrano[4,3- b ][1]benzopyranone derivatives were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. • Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas several compounds showed potent inhibitory activities toward MAO-B. • Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE. • This report is the first to identify pyrano[4,3- b ][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. Abstract A series of eighteen pyrano[4,3- b ][1]benzopyranone derivatives (1a - 9b) were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas compounds 2a , 2b , 4a , 4b , 5a , 5b , 6a , 6b , 8a and 8b showed potent inhibitory activities toward MAO-B. Intriguingly, compounds 5a , 5b , and 8a showed inhibitory activities comparable to pargylin, used as a positive control for MAO-B. Substitution of butoxy at the C3 position or of chlorine at the C8 position of pyrano[4,3- b ][1]benzopyranone increased the inhibitory activity of the compound toward MAO-B. The results of a molecular docking study supported this structural effect. Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE, with exo type compounds bearing a butoxy group, such as compounds 2b , 5b and 8b , showing weak but distinct inhibitory activities toward BChE. This report is the first to identify pyrano[4,3- b ][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. 3-Butoxy-8-chloro-pyrano[4,3-b][1]benzopyranone (5b) may be useful as a lead compound for the development of MAO-B inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel tacrine-coumarin hybrids were designed, synthesized and evaluated. • All compounds were evaluated for their AChE and BChE inhibitory activities. • Compound 8e and 8m showed the most potent anti-AChE and anti-BChE activity (IC 50 = 27 nM and 6 nM, respectively). • Compound 8e also showed good BACE1 inhibitory activity and neuroprotectivity. • Compound 8e significantly improved the learning and memory impairment in rat induced by scopolamine. Abstract A new series of tacrine-coumarin hybrids linked to 1,2,3-triazole were designed, synthesized, and tested as potent dual binding site cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD). Among them, compound 8e was the most potent anti-AChE derivative (IC 50 = 27 nM) and compound 8m displayed the best anti-BChE activity (IC 50 = 6 nM) much more active than tacrine and donepezil as the reference drugs. Compound 8e was also evaluated for its BACE1 inhibitory activity and neuroprotectivity against PC12 cells exposed to Aβ 25-35 which indicated low activity. Finally, in vivo studies by Morris water maze task showed that compound 8e significantly reversed scopolamine-induced memory deficit in rats. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • We designed and synthesized some new dispiropyrrolodinyl-oxindole -based alkaloids. • We evaluated the newly synthesized analogues as cholinesterase inhibitors. • Some of the new chemical entities showed promising BuChE inhibitors. • The bio-results were validated by 2D-QSAR study. • The achieved model can be adopted for optimizing hits of high potency. Abstract In this work, we describe the regioselective synthesis of some new dispiro[ indene -2,3′- pyrrolidine -2′,3″- indoline ]-1,2″(3H)-dione 4 - 29 attributable to the previously described methods. All the new chemical entities were assessed in-vitro as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes; while no significant inhibitory activity for the tested compounds were assigned on AChE, compounds 4 , 27 , 29 , 28 and 15 were the most active against BChE enzyme with IC 50 = 13.7 µM, 21.8 µM, 22.1 µM, 22.9 µM and 24.9 µM respectively compared to Donepezil (IC 50 = 0.72 µM). Compound 4 was found to have a mixed type mode of inhibition, the bioactivity of the new chemical entities (N = 26, n = 5, R 2 = 0.893, R 2 cvOO = 0.831, R 2 cvMO = 0.838, F = 33.32, s2 = 0.003) was elucidated via a statistically significant QSAR model utilizing CODESSA-Pro software that validated the observed results. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel p-aminobenzoic acid derivatives were designed, synthesized and characterized. • The compounds exhibited significant inhibitory potential against AChE and BChE. • Compound 22 exhibited significant improvements in working and reference memory. • The ex vivo study confirmed the ability of compound 22 to cross the BBB. • The in silico studies demonstrated the binding to active pocket in a stable manner. Abstract Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE. [ABSTRACT FROM AUTHOR]

Graphical abstract Highly functionalized 2-amino-4 H -pyrans were achieved in excellent yields and assessed for their potential as inhibitors of AD. Compound bearing nitro groups on both the aryl rings showed the highest activity and this is also supported by its inhibition mechanisms on AChE and BChE receptors. Highlights • Novel highly functionalized 2-amino-4 H -pyrans were achieved in excellent yields. • The structure of 4 H -pyrans were confirmed by FT-IR and NMR spectroscopic studies. • The compounds were evaluated as potential agents for Alzheimer's disease. • Molecular docking simulation was performed to disclose the mechanism of inhibition. Abstract Novel highly functionalized 2-amino-4 H -pyrans were achieved in excellent yields under simple grinding at ambient temperature and were assessed for their potential for treating Alzheimer's disease (AD). The 2-amino-4 H -pyran bearing nitro groups on both the aryl rings showed the highest activity, with an IC 50 of 1.98 ± 0.09 µM against acetylcholinesterase (AChE) and 10.62 ± 0.21 µM against butyrylcholinesterase (BChE), the inhibition mechanisms on AChE and BChE receptors were revealed by means of molecular docking simulations. [ABSTRACT FROM AUTHOR]

Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a-i, containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC 50 values of 6.72 ± 0.09 and 8.91 ± 0.08 μM, respectively. In addition, compound 11e displayed not only excellent inhibition of self- and Cu 2+ -induced Aβ 1-42 aggregation (91.85% and 85.62%, respectively) but also induced disassembly of self- and Cu 2+ -induced Aβ fibrils (84.54% and 83.49% disaggregation, respectively). Moreover, 11e significantly reduced tau protein hyperphosphorylation induced by Aβ 25-35 , and also exhibited good inhibition of platelet aggregation. A neuroprotective assay demonstrated that pre-treatment of PC12 cells with 11e significantly decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins (Bcl-2, Bax and caspase-3) and inhibited RSL3-induced PC12 cell ferroptosis. Furthermore, hCMEC/D3 and hPepT1-MDCK cell line permeability assays indicated that 11e would have optimal blood-brain barrier and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11e significantly attenuated learning and memory impairment in an AD mice model. Toxicity experiments with the compound did not reveal any safety concerns. Notably, 11e significantly reduced β-amyloid precursor protein (APP) and β-site APP cleaving enzyme-1 (BACE-1) protein expression in brain tissue of scopolamine-treated mice. Taken together, these outstanding properties qualified compound 11e as a promising multi-target candidate for AD therapy, worthy of further studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A series of new 1,2,3-triazole linked coumarinopyrazole conjugates 4a-e and 5a-e have been synthesized via the Copper(I)-catalysed Alkyne-Azide Cycloaddition (CuAAC). Going through the reaction of compound 2 with the 3-propargyl bromide gave a mixture of propargylated regioisomers 3 + 3′ used as a dipolarophile to access to triazoles 4a-e and 5a-e . The structures of the prepared cycloadducts were determined by 1 H, 13 C and 2D-NMR techniques and by HRMS analysis. All the synthesized derivatives have been evaluated for their anticholinesterase, anti-5-lipoxygenase, anti-tyrosinase, and cytotoxic activities. [ABSTRACT FROM AUTHOR]

A series of benzofuran-2-carboxamide- N -benzyl pyridinium halide derivatives ( 6a-o ) are synthesized as new cholinesterase inhibitors. The synthetic pathway involves the reaction of salicylaldehyde derivatives and ethyl bromoacetate, followed by hydrolysis and amidation with 3- and 4-picolyl amine. Subsequently, N -((pyridin-4-yl) methyl) benzofuran-2-carboxamide and substituted N -((pyridin-3-yl) methyl) benzofuran-2-carboxamides reacts with benzyl halides to afford target compounds ( 6a-o) . The chemical structures of all derivatives were confirmed by spectroscopic methods. The studies reveal that some of the synthesized compounds are potent butyrylcholinesterase inhibitors with IC 50 values in the range of 0.054–2.7 µM. In addition, good inhibitory effects on Aβ self-aggregation are observed for 6h and 6k (33.1 and 46.4% at 100 µM, respectively). [ABSTRACT FROM AUTHOR]

A regio and stereo- selective synthesis of hitherto unexplored hybrid heterocyclic system comprising spiropyrrolidine, indolizino[6,7- b ]indole units in good to excellent yields, has been developed via three component 1,3-dipolar cycloaddition and concomitant trifluoroacetic acid catalyzed Pictet-Spengler cyclization with paraformaldehyde. The newly synthesized compounds were evaluated for their in vitro acetylcholinesterase (AChE) and butylcholinesterase (BChE) enzyme inhibitory activities. Most of the synthesized compounds showed good inhibitory activity, among them, compounds 4d and 4g displayed highest potency against AChE (IC 50 1.88 and 1.98 μM), and BChE (IC 50 18.32 and 10.21 μM) enzyme, respectively than the standard drug, galanthamine. Molecular modeling simulation was investigated for the most active compounds 4d and 4g on AChE and BChE enzymes to disclose the binding and orientation of these molecules into active site of respective receptors. [ABSTRACT FROM AUTHOR]

A set of triterpenoids with different grades of oxidation in the lupane skeleton were prepared and evaluated as cholinesterase inhibitors. Allylic oxidation with selenium oxide and Jones’s oxidation were employed to obtain mono-, di- and tri-oxolupanes, starting from calenduladiol ( 1 ) and lupeol ( 3 ). All the derivatives showed a selective inhibition of butyrylcholinesterase over acetylcholinesterase (BChE vs . AChE). A kinetic study proved that compounds 2 and 9 , the more potent inhibitors of the series, act as competitive inhibitors. Molecular modeling was used to understand their interaction with BChE, the role of carbonyl at C-16 and the selectivity towards this enzyme over AChE. These results indicate that oxidation at C-16 of the lupane skeleton is a key transformation in order to improve the cholinesterase inhibition of these compounds. [ABSTRACT FROM AUTHOR]

The synthesis of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylates ( 4 , 5 ) was performed via the reaction of corresponding anilines with diethyl ethoxymethylenemalonate under conventional and also microwave promoted conditions. The treatment of 4 and 5 afforded the corresponding hydrazides ( 6 and 7 ). These hydrazides were converted to the corresponding carbo(thio)amides ( 9a-f and 10a-e ) which were then subjected to an intramolecular cyclisation leading to the formation of quinolone-triazole hybrids ( 11a-f and 12a-e ). The newly synthesized compounds were screened for their biological activities such as antioxidant capacity (AC) and acetylcholinesterase Activity. Inhibition of cholinesterases is an effective method to curb Alzheimer’s disease, a progressive and fatal neurological disorder. A series of some novel quinolone derivatives were designed, synthesized, and their inhibitory effects on AChE were evaluated. We obtained our compounds and determined their anticholinesterase activities according to the Ellman’s method. 9b and 10c showed the best AChE inhibition with 0.48 ± 0.02 and 0.52 ± 0.07, respectively. Docking studies were performed for the most active compounds ( 9b , 10c ) and interaction modes with enzyme active sites were determined. As a result of these studies, a strong interaction between these compounds and the active sites of AChE enzyme was revealed. [ABSTRACT FROM AUTHOR]

Three new norditerpenoids alkaloids, 1 β -hydroxy,14 β -acetyl condelphine ( 1 ), jadwarine-A ( 2 ), jadwarine-B ( 3 ) along with two known alkaloids isotalatizidine hydrate ( 4 ) and dihydropentagynine ( 5 ) were isolated from medicinal plant Delphinium denudatum . The structures of natural products 1 – 5 were established on the basis of HR-EIMS, 1 H and 13 C NMR (1D & 2D) spectroscopic data as well as by comparison from literature data. The structures of compound 1 and 4 were also confirmed by single crystal X-ray diffraction studies. In - vitro AChE and BChE enzyme inhibitory activities of compounds 1 – 5 and molecular docking studies were performed to investigate the possible molecular inhibitory mechanism of the isolated natural products. Compound 2, 4 and 5 showed competitive inhibitory effects by inhibiting AChE and BChE, respectively, while 1 and 3 showed non-competitive inhibition. This work is the first report that provides a supporting evidence about the use of constituents of Delphinium denudatum in cerebral dementia and Alzheimer diseases. [ABSTRACT FROM AUTHOR]

Alzheimer is a neurodegenerative disease and requires the development of new scaffold to treat it. In this regard, thiazoles derivative are playing their significant role. In the current research paper we have focused our attention for the development of tetrasubstituted thiazole (3a-h) derivatives using domino synthesis by mixing the thiourea as a precursor, with acetophenone in the presence of iodine and tosic acid in DMSO and refluxed for 12–22 h. The structures of the newly synthesized compounds were confirmed by FTIR, 1 H NMR, 13 C NMR and EIMS analysis. Thiazole derivatives were analyzed for their biological significances against acetyl and butylcholinesterase enzymes and compound 3b and 3d were found more active against these enzyme, respectively. The mode of inhibition was determined for the potent compounds against both the enzymes. Moreover, the molecular docking studies were carried out to explore the interactive behavior of the compounds within the active pocket of enzymes. Furthermore, the derivatives (3a-h) were evaluated for their anticancer potential against HeLa cancer cell lines. Most potent inhibition was observed by compound 3b . [ABSTRACT FROM AUTHOR]

A new series of oxopyrrolidines was synthesized and evaluated for their effect on Alzheimer‘s disease by measuring their inhibitory activity against acetyl cholinesterase enzyme and amyloid β 42 protein. Most of the compounds showed good inhibitory activity with ethyl 2-(2-(2, 6-dimethylphenylcarbamoyl)- 5-oxopyrrolidin-1-yl) acetate ( V ) having the highest activity against acetyl cholinesterase with IC 50 value 1.84 ng/g tissue compared to standard donepezil 3.34 ng/g tissue. Furthermore, compound 1-((4-(4-chlorophenyl) piperazin-1-yl) methyl)-N-(2,6-dimethylphenyl)-5- oxopyrrolidine- 2-carboxamide (IIIe) displayed the highest activity against β 42 protein with IC 50 value of 11.3 Pg/g tissue compared to 18.4 Pg/g tissue of donepezil. [ABSTRACT FROM AUTHOR]

Due to the immense importance of aryl indole nucleus, herein we report the palladium-catalyzed arylation of N -substituted 2-aryl indole utilizing Suzuki-Miyaura cross coupling methodology. The biological screening for cholinesterase inhibition of the resulted biaryl indole moieties was carried out to evaluate their pharmacological potential, expecting to involve the development of new therapeutics for various inflammatory, cardiovascular, gastrointestinal and neurological diseases. This research work also involved the use of utilization of microwave-assisted organic synthesis (MAOS) for the synthesis of Bischler-Möhlau indole which is further biarylated via palladium-catalyzed cross coupling reaction. All the synthetic compounds ( 3a-n ) were tested for cholinesterase inhibition and exhibited high level of AChE inhibitory activities. Interestingly, compounds 3m and 3n were found to be dual inhibitors, however, remaining compound exhibited no inhibitory activity against BChE. The biological potential of the resulted compounds was explained on the basis of molecular docking studies, performed against AChE and BChE, exploring the probable binding modes of most potent inhibitors. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder, which affected 35 million people in the world. The most practiced approach to improve the life expectancy of AD patients is to increase acetylcholine neurotransmitter level at cholinergic synapses by inhibition of cholinesterase enzymes. A series of unreported piperidone grafted spiropyrrolidines 8 ( a-p ) were synthesized and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Therein, compounds 8h and 8l displayed more potent AChE enzyme inhibition than standard drug with IC 50 values of 1.88 and 1.37 µM, respectively. Molecular docking simulations for 8l possessing the most potent AChE inhibitory activities, disclosed its interesting binding templates to the active site channel of AChE enzymes. These compounds are remarkable AChE inhibitors and have potential as AD drugs. [ABSTRACT FROM AUTHOR]

Based on the broad spectrum of biological activities associated with organophosphates, a novel type of this class of compounds was synthesized, bearing a nitrile group, from the sodium alkoxide-catalyzed reaction of dialkylphosphites with γ-ketonitriles at 80 °C under solvent-free conditions. A reaction mechanism involving a phospha-Brook type rearrangement is proposed. Eight title compounds were investigated for their in vitro inhibitory potency and selectivity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Ellman’s spectrophotometric method. The synthesized derivatives exhibited mostly a moderate activity against both cholinesterases. The IC 50 values for BChE were in a smaller concentration range (5.96–23.35 µM) compared to those for AChE inhibition (9.61–53.74 µM). The diethyl-3-cyano-1- p -tolylpropylphosphate which displayed the higher dual inhibitory potency towards both cholinesterases could be considered as a potential candidate for developing new drugs to treat Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

A novel series of tacrine derivatives containing sulfonamide group were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The result showed that all the synthesized tacrine-sulfonamides ( VIIIa–o ) exhibited inhibitory activity on both cholinesterases. VIIIg showed the highest inhibitory activity on AChE IC 50 = 0.009 μM. This value is 220-fold greater than that of galantamine (IC 50 = 2.054 μM) and 6-fold greater than tacrine (IC 50 = 0.055 μM). VIIIf displayed the strongest inhibition of BuChE (IC 50 = 2.250 μM), which is close to donepezil (IC 50 = 2.680 μM) and 8-fold greater than that of galantamine (IC 50 = 18.130 μM) Furthermore, all of the synthesized tacrine derivatives showed higher inhibition of BuChE than that of galantamine. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were investigated for the antioxidant activity. Among them, VIIIb (IC 50 = 94.390 ± 2.310 μM) showed significantly better ABTS cation radical scavenging ability than all of the new synthesized compounds. [ABSTRACT FROM AUTHOR]

A series of novel cholinesterase inhibitors containing nitrobenzoate core structure were synthesized by a facile and efficient method. The structure of the novel compounds were fully characterized and confirmed by analytical as well as spectroscopic methods. Compound indicated as 2f was found to possess the best cholinesterase inhibitory activities of all the evaluated compounds. Results suggest that 2f is a selective acetylcholinesterase inhibitor, although it also inhibits butyrylcholinesterase at higher concentration. Kinetics inhibition result suggest that 2f is a mixed-mode inhibitor of acetylcholinesterase. In addition, it was found to have low cytotoxicity. Molecular docking on compound 2f was carried out to rationalize the observed in vitro enzymatic assay results. Most importantly, the potential of nitrobenzoate derivatives as cholinesterase inhibitor was shown through this study. In summary, we discovered nitrobenzoates as a new scaffold that may eventually yield useful compounds in treatment of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • Thiourea and benzamide derivatives of 2-aminothiazole were synthesized as anti-AD agents. • Some of the compounds were found as antioxidant, metal chelator and cholinesterase inhibitor. • Anti-inflammatory, and protective activity assessments of selected compounds have been done. • Compounds 3c , 6e , and 10e revealed good potency and safety profiles. • Thiourea derivatives can be promising scaffold for the design of new selective BChE inhibitors. In this study, two series of compounds were designed and synthesized, bearing thiourea and benzamide derivatives at position 2 of 4-subtituted-2-aminothiazole, respectively. Then, the inhibition potency of all final compounds for cholinesterase enzymes were evaluated. Among the thiourea derivatives, 3c (IC50 = 0.33 μM) was identified as the most potent and selective butyrylcholinesterase inhibitor. Additionally, benzamide derivative 10e (AChE IC50 = 1.47 and BChE IC50 = 11.40 μM) was found as a dual cholinesterase inhibitor. The type of inhibition for both compounds was determined by kinetic studies and the results showed that the compounds were mixed type inhibitors. Moreover, all title compounds were investigated in terms of their antioxidant (DPHH, ORAC) and metal chelator activities. In addition, the neuroprotective effects of selected compounds (3c , 3e , 6c , 6e and 10e) against H 2 O 2 -induced damage in the PC12 cell line were tested. The experimental findings demonstrated that thiourea-derived 6e (40.4 %) and benzamide-derived 10e (37.8 %) have a neuroprotective effect of about half as ferulic acid at 10 μM. Subsequently, the cytotoxicity of selected compounds was examined by the MTT assay, and the compounds were found not to have cytotoxic effect on the PC12 cell line in 24 h. Additionally, compounds 6e and 10e were also found to be more effective in inhibiting the release of IL-1β, IL-6, TNF-α and NO compared to other selected compounds in this study. [ABSTRACT FROM AUTHOR]

[Display omitted] • Amides derived from sclareolide showed enzymatic inhibition of 65.2% to 78.2%. • All BuChE inhibitors were more potent than positive control galantamine. • Docking studies showed important structural portion for AChE and BuChE inhibition. • Compound 15 (Ki 1.71; EC 50 > 30 μM) is a lead to treat Alzheimer's disease. • New lead for the development of new drug to treat Alzheimer's disease is reported. A series of 25 amides (15 new) derived from (3a R)-(+)-sclareolide were prepared and subjected to Ellman's assay to determine their efficacies as inhibitors for AChE or BuChE. Five amides (9 , 13 , 14 , 15 and 17) caused inhibition of one of the enzymes greater than 60%; thereby those that inhibited BuChE were more active than positive control galantamine, and they showed better K i values (1.07 to 8.49). In general, it was found that molecules holding a meta-substituted phenyl group showed a higher percentage of enzymatic inhibition. Molecular modelling calculations indicated the putative interactions of compounds with the amino acids residues of both enzymes AChE and BuChE. The cytotoxicity of compounds 9 , 13 , 14 , 15 and 17 was evaluated against a non-malignant murine embryonic fibroblast cell line (NIH 3T3). Of special note is compound 15 , as it presented the second-best K i value for BuChE (1.71), was not cytotoxic (EC 50 > 30 μM). Compound 15 also does not violate Lipinski rules, and showed permeability in the blood brain barrier, indicating that it can be considered a lead for the development of new drugs to treat Alzheimer's disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel series of AP2238-clorgiline hybrids as anti-Alzheimer agents has been designed and synthesized. • 5l showed the balanced and good inhibitory activity against AChE, BuChE and MAO-B. • 5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 μM and no acute toxicity at a dosage of 2500 mg/kg. • 5l could significantly reverse scopolamine-induced memory deficit in mice and penetrate the BBB. Cholinesterase and monoamine oxidase are potential targets for the therapy of Alzheimer's disease. A series of novel AP2238-clorgiline hybrids as multi-target agents were designed, synthesized and investigated in vitro for their inhibition of cholinesterases and monoamine oxidases. Many compounds displayed balanced and good inhibitory activity against AChE, BuChE and MAO-B with an obvious selective inhibitory effect on MAO-B. Among them, Compound 5l showed the most balanced potency to inhibit ChEs (ee AChE: IC 50 = 4.03 ± 0.03 μM, eq BuChE: IC 50 = 5.64 ± 0.53 μM; h AChE: IC 50 = 8.30 ± 0.04 μM, h BuChE: IC 50 = 1.91 ± 0.06 μM) and h MAO-B (IC 50 = 3.29 ± 0.09 μM). Molecular modeling and kinetic studies showed that 5l was a mixed inhibitor for both AChE and BuChE, and a competitive MAO-B inhibitor. Compound 5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 μM and no acute toxicity at a dosage of 2500 mg/kg. Moreover, 5l can improve the memory function of mice with scopolamine-induced memory impairment and have an excellent ability to cross the blood–brain barrier. Overall, these findings suggested that compound 5l could be deemed as a promising, balanced multi-target drug candidate against Alzheimer's disease. [ABSTRACT FROM AUTHOR]

A series of new α-carboline analogues modified at N 1 or N 9 positions by alkyl, benzyl and phenyl were synthesized and characterized as potential ligands for AD therapy. These compounds exhibited multifunctional neurobiological activities including anti-neuroinflammatory, neuroprotective and cholinesterase inhibition. Among them, compound 5d with good drug-like properties and no cytotoxicity, showed potent inhibitory activity against NO production (IC 50  = 1.45 μM), which could suppress the expression levels of iNOS and COX-2 in a dose-dependent manner. Further mechanism exploration indicated that compound 5d could regulate the NF-κB signaling pathway by decreasing the phosphorylation of IκB-α and p65. Notably, compound 5d could effectively decrease the LPS-induced aberrations in zebrafish. Compounds 3b, 4f, 5c, 5g, 5m and 6i exhibited potential neuroprotective activity (cell viability > 70 %) in the H 2 O 2 -induced PC-12 neuronal death model and rescued the SOD activity. In particular, compounds 3b, 4f, and 5g activated the Nrf2 signaling pathway, and improved the expressions of antioxidant proteins NQO-1 and HO-1, which alleviated the head cell apoptosis in zebrafish. Additionally, compound 6i exhibited potential inhibitory activity against BuChE with IC 50 of 0.77 μM. Overall, this work provided some lead compounds based on α-carboline used for AD therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Based on a broad spectrum of biological activities of rhodanines, we synthesized aromatic amides and esters of 2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid (rhodanine-3-acetic acid) via carbodiimide- or PCl 3 -mediated coupling. Both esters and amides were investigated for their in vitro inhibitory potency and selectivity against acetylcholinesterase (AChE) from electric eel and butyrylcholinesterase (BChE) from equine serum using Ellman’s spectrophotometric method. The derivatives exhibited mostly a moderate activity against both cholinesterases. IC 50 values for AChE were in a closer concentration range of 24.05–86.85 μM when compared to BChE inhibition (7.92–227.19 μM). The esters caused the more efficient inhibition of AChE than amides and parent acid. The esterification and amidation of the rhodanine-3-acetic acid increased inhibition of BChE, even up to 26 times. Derivatives of 4-nitroaniline/phenol showed the activity superior to other substituents (H, Cl, CH 3 , OCH 3 , CF 3 ). Rhodanines produced a balanced inhibition of both cholinesterases. Seven derivatives produced the more potent inhibition of AChE than rivastigmine, a clinically used drug; additional three compounds were comparable. Two amides exceeded inhibitory potency of rivastigmine towards BChE. Importantly, this is the first evidence that rhodanine-based compounds are able to inhibit BChE. [ABSTRACT FROM AUTHOR]

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE ( Ee AChE) and equine serum BuChE ( Eq BuChE) in order to determine the compounds IC 50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC 50 of 89.5 μM for Ee AChE and 153.8 μM for Eq BuChE, (2a) was identified as a second hit with an IC 50 of 108.4 μM ( Ee AChE) and 277.8 μM ( Eq BuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, ( R )- (1f) along with 3 other analogues (also as the R -enantiomer) were docked into both Rh AChE and h BuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark. [ABSTRACT FROM AUTHOR]