Selective Butyrylcholinesterase Inhibitors Research Articles

Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies

The symptomatic and disease-modifying effects of butyrylcholinesterase (BuChE) inhibitors provide an encouraging premise for researching effective treatments for Alzheimer's disease. Here, we examined a series of compounds with a new chemical scaffold based on 3-(cyclohexylmethyl)amino-2-hydroxypropyl, and we identified a highly selective hBuChE inhibitor (29). Based on extensive in vitro and in vivo evaluations of the compound and its enantiomers, (R)-29 was identified as a promising candidate for further development. Compound (R)-29 is a potent hBuChE inhibitor (IC50 = 40 nM) with selectivity over AChE and relevant off-targets, including H1, M1, α1A and β1 receptors. The compound displays high metabolic stability on human liver microsomes (90% of the parent compound after 2 h of incubation), and its safety was confirmed through examining the cytotoxicity on the HepG2 cell line (LC50 = 2.85 μM) and hERG inhibition (less than 50% at 10 μM). While (rac)-29 lacked an effect in vivo and showed limited penetration to the CNS in pharmacokinetics studies, compound (R)-29 exhibited a procognitive effect at 15 mg/kg in the passive avoidance task in scopolamine-treated mice.

Molecular and Computational Analysis Identify Statins as Selective Inhibitors of Human Butyrylcholinesterase.

Cholinesterase enzyme family consists of acetylcholinesterase (AChE, 3.1.1.7), the major enzyme responsible for hydrolysis of acetylcholine at cholinergic synapses, and butyrylcholinesterase (BChE, 3.1.1.8) a detoxification enzyme of plasma. Statins are cholesterol-lowering medications utilized as protective medicaments in stroke and Alzheimer's disease, which cholinesterases are associated with. Thus, in this study, we characterized the inhibitory effects and mechanisms of common statins, rosuvastatin, atorvastatin, simvastatin and lovastatin, on human erythrocyte AChE and purified serum BChE using in vitro and in silico methods. Kinetic assays identified statins as selective non-competitive inhibitors of human serum BChE. The IC50 and Km values were found as 194.7 ± 55.2 µM and 1.03 ± 0.2 µM for rosuvastatin, 492.5 ± 55.1 µM and 7.2 ± 0.3 µM for atorvastatin, 14.2 ± 0.3 µM and 202.7 ± 23.2 µM for lovastatin, and 17.6 ± 0.1 µM and 207.2 ± 13.2 µM for simvastatin, respectively. The compounds did not display considerable inhibition against AChE. Molecular docking predicted good affinity and strong interactions with the BChE active site for atorvastatin and rosuvastatin. Current study identifies rosuvastatin as the most specific and selective inhibitor of human BChE among the tested statins. As selective inhibitors of BChE statins have the potential to be re-evaluated as medicaments due to their pleiotropic effects.

Annulated bicyclic isothioureas: identification of active and selective butyrylcholinesterase inhibitors

Structural optimization of butyrylcholinesterase inhibitors, 5-bromomethyl- and 5-iodomethyl-N,N-disubstituted 2-aminothiazolines, led to a series of their annulated bicyclic analogues, obtained by intramolecular cyclization of cycloalkenylthioureas. The most active compound in this series, cyclohepta[d]thiazol-2-amine, is a mixed-type butyryl-cholinesterase inhibitor with IC50 = 130 nm, highly selective compared to acetylcholinesterase and non-toxic at 100 μm concentrations.

New thiourea and benzamide derivatives of 2-aminothiazole as multi-target agents against Alzheimer's disease: Design, synthesis, and biological evaluation

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 H2O2-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.

Selective butyrylcholinesterase inhibition by isatin dimers and 3-indolyl-3-hydroxy-2-oxindole dimers

Polymethylene-linked isatin dimers 1a-g and 3-indolyl-3-hydroxy-2-oxindole dimers 2a-g were synthesized and are reported here as selective butyrylcholinesterase (BChE) inhibitors. The best compound from each series, 1f and 2d, showed IC50 values of 3.20 µM and 4.49 µM, respectively. Both compounds showed > 11-fold selectivity towards BChE, and mixed-type inhibition by Lineweaver-Burk analysis. These two inhibitors shared π-π stacking interactions with Trp82 and H-bonding to Gly116 and Ser198, the catalytic Ser of the enzyme triad, within the BChE active site as predicted by molecular docking. Compound 1d was also shown to be good inhibitor with an IC50 of 7.56 µM, and it shares the same pentamethylene linker as 2d. Inhibitors 1d, 1f, and 2d were predicted to have moderate, low, and moderate blood–brain barrier (BBB) permeability, respectively, making them, overall, promising lead compounds for further exploration of selective BChE inhibitors.

Design, Synthesis and Biological Evaluation of Biscarbamates as Potential Selective Butyrylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

As butyrylcholinesterase (BChE) plays a role in the progression of symptoms and pathophysiology of Alzheimer’s disease (AD), selective inhibition of BChE over acetylcholinesterase (AChE) can represent a promising pathway in treating AD. The carbamate group was chosen as a pharmacophore because the carbamates currently or previously in use for the treatment of AD displayed significant positive effects on cognitive symptoms. Eighteen biscarbamates with different substituents at the carbamoyl and hydroxyaminoethyl chain were synthesized, and their inhibitory potential toward both cholinesterases and inhibition selectivity were determined. The ability of carbamates to cross the blood–brain barrier (BBB) by passive transport, their cytotoxic profile and their ability to chelate biometals were also evaluated. All biscarbamates displayed a time-dependent inhibition with inhibition rate constants within 10−3–10−6 M−1 min−1 range for both cholinesterases, with generally higher preference to BChE. For two biscarbamates, it was determined that they should be able to pass the BBB by passive transport, while for five biscarbamates, this ability was slightly limited. Fourteen biscarbamates did not exhibit a cytotoxic effect toward liver, kidney and neuronal cells. In conclusion, considering their high BChE selectivity, non-toxicity, ability to chelate biometals and pass the BBB, compounds 2 and 16 were pointed out as the most promising compounds for the treatment of middle and late stages of AD.

Synthesis, Biological Evaluation and Machine Learning Prediction Model for Fluorinated Cinchona Alkaloid-Based Derivatives as Cholinesterase Inhibitors.

A series of 46 Cinchona alkaloid derivatives that differ in positions of fluorine atom(s) in the molecule were synthesized and tested as human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. All tested compounds reversibly inhibited AChE and BChE in the nanomolar to micromolar range; for AChE, the determined enzyme-inhibitor dissociation constants (Ki) ranged from 3.9–80 µM, and 0.075–19 µM for BChE. The most potent AChE inhibitor was N-(para-fluorobenzyl)cinchoninium bromide, while N-(meta-fluorobenzyl)cinchonidinium bromide was the most potent BChE inhibitor with Ki constant in the nanomolar range. Generally, compounds were non-selective or BChE selective cholinesterase inhibitors, where N-(meta-fluorobenzyl)cinchonidinium bromide was the most selective showing 533 times higher preference for BChE. In silico study revealed that twenty-six compounds should be able to cross the blood-brain barrier by passive transport. An extensive machine learning procedure was utilized for the creation of multivariate linear regression models of AChE and BChE inhibition. The best possible models with predicted R2 (CD-derivatives) of 0.9932 and R2(CN-derivatives) of 0.9879 were calculated and cross-validated. From these data, a smart guided search for new potential leads can be performed. These results pointed out that quaternary Cinchona alkaloids are the promising structural base for further development as selective BChE inhibitors which can be used in the central nervous system.

Design, synthesis, and biological evaluation of aromatic tertiary amine derivatives as selective butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease

Butyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17–1001) was screened and validated as a selective BChE inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, neurotoxicity assay and neuroprotective effects assay indicated two optimal compounds 17c and 19c. Both compounds showed selective BChE inhibitory (hBChE < 20 nM, eeAChE > 10 μM), good BBB permeation and primary cell safety. Besides, 17c can dose-response protect cell from Aβ1−42 induced damage. It also demonstrated that 17c and 19c were able to restore cognitive impairment in vivo test. These data suggest that 17c and 19c represent promising candidate for follow-up in the drug-discovery process against AD.

Biological evaluation, molecular modeling and dynamics simulation of phenanthrenes isolated from Bletillastriata as butyrylcholinesterase inhibitors

As part of our continuous studies on natural cholinesterase inhibitors from plant kingdom, the 95% ethanol extract from tubers of Bletillastriata showed promising butyrylcholinesterase (BChE) inhibition (IC50 = 8.6 μg/mL). The extracts with different polarities (petroleum ether, ethyl acetate, n-butanol, and water) were prepared and evaluated for their inhibition of cholinesterases. The most active ethyl acetate extract was subjected to a bioassay-guided isolation and afforded twenty-two bibenzyls and phenanthrenes (1–22). All isolates were further evaluated for their BChE inhibition activity, and five phenanthrenes presented promising capacity (IC50 < 10 μM). Further kinetic studies indicated their modes of inhibition. Compounds 6, 8, and 14 were found to be mixed-type inhibitors, while compounds 10 and 12 could be classified as non-competitive inhibitors. The potential interaction mechanism of them with BChE was demonstrated by molecular docking and molecular dynamics simulation, showing that they could interact with catalytic active site and peripheral anionic site of BChE. These natural phenanthrenes provide new scaffold for the further design and optimization, with the aim to discover new selective BChE inhibitors for the treatment of AD.

Synthesis of novel carboxamide- and carbohydrazide-benzimidazoles as selective butyrylcholinesterase inhibitors.

Selectively inhibiting butyrylcholinesterase (BChE) is hypothesized to help in the management of Alzheimer's disease (AD). Several studies have determined a correlation between the increased activity of BChE and the onset of AD. An advantage of BChE over acetylcholinesterase inhibition is that absence of BChE activity does not lead to obvious physiological disturbance. However, currently no BChE inhibitors are available commercially as potential therapeutics for AD. In our continuous effort to find potent BChE inhibitors for Alzheimer's disease, a total of 22 novel benzimidazoles with diversified substitutions were synthesized and evaluated for their anticholinesterase activities in this study. Among the synthesized compounds, 2j and 3f were found to exhibit potent and selective BChE inhibition with IC50 values of 1.13 and 1.46μM, respectively. Molecular docking studies were carried out to rationalize the observed inhibitory activities. The compounds were predicted to have high penetration across the blood-brain barrier. Moreover, cell proliferative studies were also performed to evaluate the toxicity profile of the interested compounds. Compound 3f was found to be a potent and selective butyrylcholinesterase inhibitor with an IC50 value of 1.46µM.

Design, synthesis, biological evaluation and molecular modeling of N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4yl)methyl)benzo[d][1,3] dioxole-5-carboxamides as selective butyrylcholinesterase inhibitors

Butyrylcholinesterase (BuChE) is recently regarded as a biomarker in progressed Alzheimer’s disease (AD). Development of selective BuChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Recently, we reported the N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (1) as a selective BuChE inhibitor. Subsequently, 33 analogs were synthesized and assessed by AChE/BuChE activities, indicating an optimal compound 23. Further kinetic tests suggested a competitive manner. Molecular docking and Molecular dynamics (MD) simulation showed that it interacted with several residues in active site gorge of BuChE, possibly contributing to its selectivity and competitive pattern. Moreover, it showed low cytotoxicity and high blood brain barrier (BBB) permeability. Taken together, 23 was a promising BuChE inhibitor for the treatment of AD.

Cholinesterase Inhibitory Activities and In Silico Docking Studies of Blumeatin Isolated from Blumea balsamifera L. DC.

Cholinesterase inhibition provides symptomatic treatment for neurodegenerative diseases such as Alzheimer’s disease. Commercially available drugs on the market mostly target acetylcholinesterase. However, evidence suggests that selective inhibition of butyrylcholinesterase may lead to greater efficacy with fewer side effects and slower disease progression. The aim of this research was to isolate a butyrylcholinesterase-selective inhibitor from Blumea balsamifera L. DC. In vitro cholinesterase assays were used to evaluate the inhibitory activity and mechanism of action of blumeatin. Molecular docking studies were performed to support the BuChE- selectivity of blumeatin. Blumeatin inhibited BuChE in a concentration-dependent manner, with an IC50 of 136.3 ± 12.6 μM and a selectivity ratio of 1.395 for BuChE over AChE. Additionally, the Ki of blumeatin is 10 times lower in BuChE compared to AChE. Molecular docking studies confirmed the selectivity, as revealed by the tighter hydrogen bonding of blumeatin with the BuChE’s active site. Blumeatin acts as a competitive inhibitor and a noncompetitive inhibitor of BuChE and AChE, respectively. With these results, blumeatin could be a potential lead as a drug treatment for AD because of its butyrylcholinesterase selectivity.

Design, synthesis and biological evaluation of novel pyrazolone derivatives as selective butyrylcholinesterase inhibitors with antioxidant activity against Alzheimer's disease

The butyrylcholinesterase (BuChE) has been a potent target for the treatment of the Alzheimer's disease (AD), but the selective BuChE inhibitor is still lacking in the market. In this study, the pyrazolone structure was found to be a promising pharmacophore targeting BuChE. Thus, a series of pyrazolone-based compounds 5a-p were designed, synthesized and evaluated in vitro for BuChE inhibitory activities, antioxidant activities and blood-brain barrier (BBB) permeabilities. Besides, the compounds 5g, 5h, 5i and 5o with submicromolar IC50 values as well as good BuChE selectivity were chosen to assess their cytotoxicity in PC12 cells. Among them, compound 5i was the most selective BuChE inhibitor (SI: >200) and showed the good abilities to penetrate BBB, scavenge free radicals (1.04 trolox equivalent). Based on above results, compound 5i was selected for molecular docking studies to explain the BuChE selectivity and was considered as a promising lead compound for further investigation in the treatment of AD.

Discovery of novel β-carboline derivatives as selective AChE inhibitors with GSK-3β inhibitory property for the treatment of Alzheimer's disease

The natural product harmine, a representative β-carboline alkaloid from the seeds of Peganum harmala L. (Zygophyllaceae), possesses a broad spectrum of biological activities. In this study, a novel series of harmine derivatives containing N-benzylpiperidine moiety were identified for the treatment of Alzheimer's disease (AD). The results showed that all the derivatives possessed significant anti-acetylcholinesterase (AChE) activity and good selectivity over butyrylcholinesterase (BChE). In particular, compound ZLWH-23 exhibited potent anti-AChE activity (IC50 = 0.27 μM) and selective BChE inhibition (IC50 = 20.82 μM), as well as acceptable glycogen synthase kinase-3 (GSK-3β) inhibition (IC50 = 6.78 μM). Molecular docking studies and molecular dynamics simulations indicated that ZLWH-23 could form stable interaction with AChE and GSK-3β. Gratifyingly, ZLWH-23 exhibited good selectivity for GSK-3β over multi-kinases and very low cytotoxicity towards SH-SY5Y, HEK-293T, HL-7702, and HepG2 cell lines. Importantly, ZLWH-23 displayed efficient reduction against tau hyperphosphorylation on Ser-396 site in Tau (P301L) 293T cell model. Collectively, harmine-based derivatives could be considered as possible drug leads for the development of AD therapies.

Halogenated Coumarin-Chalcones as Multifunctional Monoamine Oxidase-B and Butyrylcholinesterase Inhibitors.

A series of halogenated coumarin–chalcones were synthesized, characterized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) were evaluated. Compound CC2 most potently inhibited MAO-B with an IC50 value of 0.51 μM, followed by CC1 (IC50 = 0.69 μM), with a selectivity index (SI) of >78.4 and >58.0, respectively, over MAO-A. However, none of the compounds effectively inhibited MAO-A, AChE, and BChE, except for CC2 and CC3 inhibiting BChE with IC50 values of 7.00 (SI > 5.73 over AChE) and 11.8 μM, respectively. CC1 and CC2 were found to be reversible and competitive inhibitors of MAO-B, with Ki values of 0.50 ± 0.06 and 0.53 ± 0.04 μM, respectively, and CC2 was also a reversible and competitive inhibitor of BChE, with a Ki value of 2.84 ± 0.09 μM. The parallel artificial membrane permeability assay (PAMPA) method showed that lead candidates can cross the blood–brain barrier (BBB). The in vitro toxicity analysis on the Vero cell line (Normal African green monkey kidney epithelial cells) by MTT confirmed that both CC1 and CC2 were nontoxic up to 100 μg/mL, which is almost equivalent to 100 times of their effective concentration used in biological studies. In addition, CC1 and CC2 attenuated H2O2-induced cellular damage via their reactive oxygen species (ROS) scavenging effect. These results suggest that CC1 and CC2 are selective and competitive inhibitors of MAO-B, and that CC2 is a selective and competitive inhibitor of BChE. Molecular docking studies of lead compounds provided the possible type of interactions in the targeted enzymes. Based on the findings, both compounds, CC1 and CC2, can be considered plausible drug candidates against neurodegenerative disorders.

Stable triterpenoid iminium salts and their activity as inhibitors of butyrylcholinesterase

Amides derived from platanic acid (30-nor-lupane skeleton) were converted in two steps into 21-aza-17,19-ethano-19-nor-urs-20-en-21-ium chlorides. These ursane-skeleton iminium salts are first in their class, and some of them proved as selective inhibitors of the enzyme butyrylcholinesterase while holding no inhibitory activity for acetylcholinesterase.

Synthesis, characterization, crystal and molecular structure and theoretical study of N-(naphthalen-1-yl)-2-(piperidin-1-yl) acetamide, a selective butyrylcholinesterase inhibitor

In this study, we reported for the first time the crystalline and molecular structure of the compound N-(naphthalen-1-yl) -2- (piperidin-1-yl) acetamide. The synthesis of the compound was carried out by amidation using a coupling reagent (N, N'-diisopropylcarbodiimide) and subsequently amination. The compound was experimentally characterized by UV-visible spectroscopy, 13C-NMR, 1H-NMR, melting point, and X-ray diffraction technique. In addition, we include here, theoretical studies on boundary molecular orbitals, descriptors global reactivity, natural bond orbital analysis, Hirshfeld surface analysis, energy framework and molecular docking. Interestingly, acetamide shows a keto form in the solid state, as reported in similar monosubstituted acetamide compounds. The dihedral angles are negligible, being essentially coplanar between the fragment. Additionally, inhibitory activity studies were carried out for the enzymes acetylcholinesterase and butyrylcholinesterase, obtaining an IC50 of 426.14 ± 18.54 µM and 5.12 ± 0.02 µM, respectively, thus having significant selectivity for butyrylcholinesterase with an IC50 lower than that reported for the reference compound galantamine (7.96 ± 0.8 µM). Our consistent molecular coupling analyzes show the formation of a more stable complex between compound 5 and butyricholinesterase due to the complementary interactions of compound 5′s naphthyl ring with residues Trp 231 and Phe 329 compared to the complex formed with acetylcholinesterase.

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE.

A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.

Novel chrysin derivatives as hidden multifunctional agents for anti-Alzheimer's disease: design, synthesis and in vitro evaluation

Alzheimer's disease (AD) is the most common type of dementia, the exact etiology of the disease has not been known yet. The use of single-target drugs limits the efficacy of drugs and has certain side effects. In this study, the ‘hidden’ multi-target strategy was used in combination with chrysin's metal chelating site and rivastigmine's anti-cholinesterase pharmacophore to form an ester, which improves the hydrophobicity and protects the phenolic hydroxyl group at the same time. Four derivatives (1-4) were synthesized as the hidden multifunctional agents for AD therapy. Most of the compounds displayed good activities of anti-cholinesterase, antioxidant, appropriate blood brain barrier (BBB) penetration and certain inhibitory activity of β-amyloid (Aβ) aggregation. Compound 3 was demonstrated as the highest selective butyrylcholinesterase (BuChE) inhibitor and targeted both the catalytic active site (CAS) and the peripheral anion site (PAS). And it could be hydrolyzed by BuChE to release chrysin with good ability to chelate Cu2+ and Fe2+. At the same time, phenol fragment can exert its good antioxidant effect. Overall, these findings demonstrated that compound 3 might be considered as a potential hidden multifunctional candidate in the therapy of AD.

Ugi Reaction Synthesis of Oxindole-Lactam Hybrids as Selective Butyrylcholinesterase Inhibitors.

Molecular hybridization is a valuable approach in drug discovery. Combining it with multicomponent reactions is highly desirable, since structurally diverse libraries can be attained efficiently in an eco-friendly manner. In this work, isatin is used as the key building block for the Ugi 4-center 3-component reaction synthesis of oxindole-lactam hybrids, under catalyst-free conditions. The resulting oxindole-β-lactam and oxindole-γ-lactam hybrids were evaluated for their potential to inhibit relevant central nervous system targets, namely cholinesterases and monoamine oxidases. Druglikeness evaluation was also performed, and compounds 4eca and 5dab exhibited great potential as selective butyrylcholinesterase inhibitors, at the low micromolar range, with an interesting predictive pharmacokinetic profile. Our findings herein reported suggest oxindole-lactam hybrids as new potential agents for the treatment of Alzheimer's disease.