Potent Acetylcholinesterase Inhibitors Research Articles

Two Lycopodium alkaloids from the aerial parts of Huperzia phlegmaria

Background: Huperzia phlegmaria has been used to enhancing memory and alleviate brain disorders. It contains high amount of alkaloids, which are potent acetylcholinesterase (AChE) inhibitor. Materials and Methods: Lycopodium alkaloids from aerial parts of H. phlegmaria were isolated by chromatographic methods. Their structures were elucidated by spectroscopic methods, including mass spectrometry and nuclear magnetic resonance. AChE inhibitory effect of isolated compounds in vitro was evaluated using Ellman's assay. Results: These compounds were identified as fawcettidine and 12-epilycodoline N-oxide. Two compounds showed moderately AChE inhibitory effects with IC50values of 33.11 μg/mL and 64.56 μg/mL, respectively. Conclusion:These isolated compounds could be promising drugs for the treatment of Alzheimer's disease.

Discovery of novel dual-active 3-(4-(dimethylamino)phenyl)-7-aminoalcoxy-coumarin as potent and selective acetylcholinesterase inhibitor and antioxidant

A series of 3-substituted-7-aminoalcoxy-coumarin was designed and evaluated as cholinesterase inhibitors and antioxidants. All compounds were effective in inhibiting AChE with potencies in the nanomolar range. The 3-(4-(dimethylamino)phenyl)-7-aminoethoxy-coumarin (6a) was considered a hit, showing good AChE inhibition potency (IC50 = 20 nM) and selectivity (IC50 BuChE/AChE = 354), quite similar to the reference drug donepezil (IC50 = 6 nM; IC50 BuChE/AChE = 365), also presenting antioxidant properties, low citotoxicity and good-predicted ADMET properties. The mode of action (mixed-type) and SAR analysis for this series of compounds were described by means of kinetic and molecular modeling evaluations.

Dihydroquinoline Carbamate DQS1-02 as a Prodrug of a Potent Acetylcholinesterase Inhibitor for Alzheimer’s Disease Therapy: Multigram-Scale Synthesis, Mechanism Investigations, in Vitro Safety Pharmacology, and Preliminary in Vivo Toxicology Profile

We previously characterized a set of potent pseudo-irreversible inhibitors of acetylcholinesterase (AChE) based on a redox prodrug strategy. Among the various synthesized prodrugs, compound 1, namely DQS1-02, displayed favorable physicochemical properties and was chosen to achieve the necessary prerequisite investigations prior to preclinical evaluation. Herein, we first report a practical multigram-scale nine-step synthesis of prodrug 1 with a good overall yield (18%) as well as a full investigation on the inhibition mechanism of AChE by the parent drug 2 by means of UV–vis spectroscopy, NMR, and tandem mass spectrometry. In the second part, we describe the ADME properties of DQS1-02, the safety pharmacology of both compounds 1 and 2, and the preliminary results of an in vivo toxicology study in rats. Last but not the least, we also demonstrated that AChE inhibitor 2 was highly selective for AChE, whereas the corresponding prodrug 1 proved to be remarkably safe, making it a valuable preclinical candidate.

In vitro and in silico evaluation of fucosterol from Sargassum horridum as potential human acetylcholinesterase inhibitor

The fucosterol has been reported numerous biological activities. In this study, the activity in vitro of the fucosterol from Sargassum horridum as potential human acetylcholinesterase inhibitor was evaluated. The structural identification was obtained by nuclear magnetic resonance (NMR) spectroscopy and based on experimental data, we combined docking and molecular dynamics simulations coupled to the molecular-mechanics-generalized-born-surface-area approach to evaluating the structural and energetic basis for the molecular recognition of fucosterol and neostigmine at the binding site of acetylcholinesterase (AChE). In addition, the Lineweaver–Burk plot showed the nature of a non-competitive inhibition. The maximum velocity (Vmax) and the constant of Michaelis–Menten (Km) estimated for fucosterol (0.006 µM) were 0.015 1/Vo (ΔA/h and 6.399 1/[ACh] mM−1, respectively. While, for neostigmine (0.14 µM), the Vmax was 0.022 1/Vo (ΔA/h) and Km of 6.726 1/[ACh] mM−1, these results showed a more effective inhibition by fucosterol respect to neostigmine. Structural analysis revealed that neostigmine reaches the AChE binding site reported elsewhere, whereas fucosterol can act as a no-competitive and competitive acetylcholinesterase inhibitor, in agree with kinetic enzymatic experiments. Binding free energy calculations revealed that fucosterol reaches the acetylcholinesterase binding site with higher affinity than neostigmine, which is according to experimental results. Whereas the per-residue decomposition free energy analysis let us identify crucial residues involved in the molecular recognition of ligands by AChE. Results corroborate the ability of theoretical methods to provide crucial information at the atomic level about energetic and structural differences in the binding interaction and affinity from fucosterol with AChE.Communicated by Ramaswamy H. Sarma

Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors.

A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-O-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer’s disease patient brains. Many of them displayed lower inhibitory concentrations of EeAChE (IC50 = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC50 = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against HsAChE and was found to be even more active than donepezil and inhibited HsAChE better than EeAChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme.

Biologically active compounds from two members of the Asteraceae family: Tragopogon dubius Scop. and Tussilago farfara L.

Tragopogon dubius and Tussilago farfara are consumed as vegetables and used in folk medicine to manage common diseases. Herein, the chemical compositions and biological activities of different leaf extracts (ethyl acetate, methanol, and water) of T. dubius and T. farfara were evaluated. The antibacterial, antifungal, and antioxidant abilities of the extracts were tested using different assays including free radical scavenging, reducing power, phosphomolybdenum, and metal chelating assays. Enzyme inhibitory potentials were evaluated against cholinesterases, tyrosinase, α-amylase and α-glucosidase. Complexes of bioactive compounds (chlorogenic and rosmarinic acid) were docked into the enzymatic cavity of α-glucosidase and subjected to molecular dynamic calculation, enzyme conformational stability, and flexibility analysis. T. dubius and T. farfara extracts showed remarkable antioxidant potentials. Ethyl acetate extracts of T. dubius and T. farfara were the most potent inhibitors of acetylcholinesterase and butyrylcholinesterase. T. dubius ethyl acetate extract and T. farfara methanolic extract showed noteworthy activity against α-glucosidase. High performance liquid chromatography analysis revealed the abundance of some phenolic compounds including chlorogenic and rosmarinic acids. Ethyl acetate extract of T. dubius showed notable antifungal activity against all strains. Docking studies showed best pose for chlorogenic acid was stabilized by a network of hydrogen bonds with residues Asp1157, Asp1279, whereas rosmarinic acid showed several hydrogen bonds with Asp1157, Asp1420, Asp1526, Lys1460 and Trp1369. This study further validates the use of T. dubius and T. farfara in traditional medicine, as well as act as a stimulus for further studies for future biomedicine development.Communicated by Ramaswamy H. Sarma

Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory

Based on the Gaussian-based quantitative structure-activity relationship (QSAR) and virtual screening (VS) processes, some promising acetylcholinesterase inhibitors (AChEIs) having antioxidant potential were designed synthesized, characterized, and evaluated for their ability to enhance learning and memory. The synthesized phenyl benzoxazole derivatives exhibited significant antioxidant potential and AChE inhibitory activity, whereas the antioxidant potential of compound 34 (49.6%) was observed significantly better than standard donepezil (<10%) and parallel to ascorbic acid (56.6%). Enzyme kinetics study of most potent compound 34 (AChE IC50 = 0.363 ± 0.017 μM; Ki = 0.19 ± 0.03 μM) revealed the true nature and competitive type of inhibition on AChE. The compound 34 was further assessed for in vivo and ex vivo studies and the results showed the significant reversal of cognitive deficits and antioxidant potential at the dose of 5 mg/kg comparable to standard drug donepezil.

Design, synthesis and cholinesterase inhibitory activity of α-mangostin derivatives

α-mangostin, a polyphenol xanthone derivative, was mainly isolated from pericarps of the mangosteen fruit (Garcinia mangostana L.). In present investigation, a series of derivatives were designed, synthesised and evaluated in vitro for their inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the synthesised xanthones, compounds 1, 9, 13 and 16 showed AChE selective inhibitory activity, 15 was a BuChE selective inhibitor while 2, 3, 5, 6, 7, 12 and 14 were dual inhibitors. The most potent inhibitor of AChE was 16 while 5 was the most potent inhibitor of BuChE with IC50 values of 5.26 μM and 7.55 μM respectively.

Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer’s agents

A novel series of benzylpyridinium-based benzoheterocycles (benzimidazole, benzoxazole or benzothiazole) were designed as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The title compounds 4a-q were conveniently synthesized via condensation reaction of 1,2-phenylenediamine, 2-aminophenol or 2-aminothiophenol with pyridin-4-carbalehyde, followed by N-benzylation using various benzyl halides. The results of in vitro biological assays revealed that most of them, especially 4c and 4g, had potent anticholinesterase activity comparable or more potent than reference drug, donepezil. The kinetic study demonstrated that the representative compound 4c inhibits AChE in competitive manner. According to the ligand-enzyme docking simulation, compound 4c occupied the active site at the vicinity of catalytic triad. The compounds 4c and 4g were found to be inhibitors of Aβ self-aggregation as well as AChE-induced Aβ aggregation. Meanwhile, these compounds could significantly protect PC12 cells against H2O2-induced injury and showed no toxicity against HepG2 cells. As multi-targeted structures, compounds 4c and 4g could be considered as promising candidate for further lead developments to treat Alzheimer’s disease.

Identification of New Chromenone Derivatives as Cholinesterase Inhibitors and Molecular Docking Studies

Alzheimer's Disease (AD) is the leading cause of dementia among the aging population. This devastating disorder is generally associated with the gradual memory loss, specified by a decrease of acetylcholine level in the cortex hippocampus of the brain due to hyperactivation of cholinesterases (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). Therefore, inactivation of AChE and BChE by inhibitors can increase the acetylcholine level and hence may be an encouraging strategy for the treatment of AD and related neurological problems. In this contribution, two series of chromenone-based derivatives were tested by Ellmann's calorimetric method for AChE and BChE inhibition. All the compounds showed inhibitory activity against cholinesterases and some of them exhibited dual inhibition of AChE as well as BChE. The most potent inhibitor of AChE was 2l having an IC50 value of 0.08 ± 0.03 µM, while 3q inhibited the BChE with an IC50 value of 0.04 ± 0.01 µM. In case of dual inhibition, 3h showed an inhibitory concentration of 0.15 ± 0.01 µM for AChE, and 0.09 ± 0.01 µM for BChE. Molecular docking studies were performed to explore the probable binding modes of the most potent dual inhibitors. It can be hypothesized that the inhibitors are able to target cholinesterase pathways and may emerge as a suitable outset for the further development process.

Design, synthesis, cholinesterase inhibition and molecular modelling study of novel tacrine hybrids with carbohydrate derivatives.

A series of hybrids containing tacrine linked to carbohydrate-based moieties, such as d-xylose, d-ribose, and d-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50 scale. Most of the d-xylose derivatives (6a-e) were selective for AChE and the compound 6e (IC50 = 2.2 nM for AChE and 4.93 nM for BuChE) was the most active compound for both enzymes. The d-galactose derivative 8a was the most selective for AChE exhibiting an IC50 ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely 7a (d-ribose derivative) and 6b (d-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinski's rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II.

Antioxidant, anti-diabetic, acetylcholinesterase inhibitory potential and estimation of alkaloids (lycorine and galanthamine) from Crinum species: An important source of anticancer and anti-Alzheimer drug

Crinum L. (Amaryllidaceae J.St. Hil.) is a bulbous monocot well known for its ornamental value and medicinal properties. Aqueous and methanolic leaf extracts of twelve Crinum genotypes were evaluated for their phytochemicals, antioxidants, in vitro anti-diabetic and acetyl cholinesterase (AChE) inhibitory activities. Maximum total phenolic content (TPC) (86.18 ± 0.61 mg TAE g−1 extract) was exhibited by C. asiaticum form 2 whereas maximum total alkaloid content (TAC) (10.81 ± 0.22 mg CoE g−1 extract), total flavonoid content (TFC) (145.06 ± 3.95 mg CE g−1 extract) and TTC (436.55 ± 3.70 mg CE g−1 extract) content were recorded for C. x powelii. The antioxidant activities were determined by 2, 2′-azinobis 3-ethylbenzthiazoline]-6-sulfonic acid (ABTS), 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP) and phosphomolybdenum assays. Methanol extract of C. asiaticum form 2 had the highest FRAP (462.81 ± 1.98 mg Fe II g−1 extract), phosphomolybdenum (116.03 ± 3.80 mg AAE g−1 extract) and DPPH radical scavenging activities (111.54 ± 2.03 mg TE g−1 extract). ABTS radical scavenging activity was greatest in aqueous extract of C. latifolium (39.65 ± 0.91 mg TE g−1 extract). RP-HPLC analysis revealed the highest phenolics in C. asiaticum form 1. Amaryllidaceae alkaloids, galanthamine (GAL) and lycorine (LY) were recorded the highest in C. latifolium (721.3 ± 4.96 μg g−1 dry weight and C. solapurense (3717.0 ± 9.40 μg g−1 DW), respectively. C. jagus revealed the highest inhibition of α-amylase (60.30%) and α-glucosidase (94.04%). AChE inhibition was maximum (76.52%) in the methanol extract of C. latifolium. This study constitutes the first comparative account of antioxidants, phenolic profiling, anti-diabetic potential and simultaneous quantification of anti-Alzheimer and anticancer drugs, viz. GAL and LY, respectively from Crinum genotypes.

STUDY OF IN VIVO PHARMACOKINETIC DRUG INTERACTIONS OF CURCUMIN ON TACRINE

Objective: Tacrine is a potent acetylcholine esterase inhibitor (AChEI), and curcumin has been recently proven to possess AChEI, amyloid β aggregation inhibitory activity in addition to its diverse pharmacodynamic nature. Tacrine undergoes biological transformation by cytochrome P450 (CYP 1A2) to a hydroxy metabolite, which is hepatotoxic. Curcumin is known for its inhibitory nature for various metabolic enzymes along with CYP1A2. The present study was undertaken to evaluate the influence of curcumin on the disposition kinetics of tacrine and to assess its impact on dosage regimen.Methods: It was hypothesized that the simultaneous administration of curcumin and tacrine can minimize the toxicity along with increased absorption of tacrine and curcumin into the biological system during the treatment of Alzheimer’s patients.Results and Discussion: Hence, an attempt was made to develop a simple, precise, accurate, and cost-effective reversed-phase high-performance liquid chromatography method for simultaneous determination of curcumin and tacrine and also to estimate the effect of curcumin on absorption of tacrine, in rat plasma.Conclusion: Concomitant administration of curcumin with tacrine improved the parameters such as Cmax and AUC, which indicates that the curcumin would improve the absorption of tacrine.

Establishment of a quantitative bioanalytical method for an acetylcholinesterase inhibitor Ethyl 3-(2-(4-fluorophenyl) amino)-4-phenylthiazol-5-yl)-3-oxopropanoate including its physicochemical characterization and in vitro metabolite profiling using Liquid Chromatography-Mass Spectrometry

Ethyl 3-(2-(4-fluorophenyl)amino)-4-phenylthiazo)-5-yl)-3-oxopropanoate is a novel molecule with potent acetylcholinesterase inhibition property. In this research, we have developed a rapid and selective RP-HPLC bioanalytical method for quantitative measurement of the molecule. The method has been validated following the USFDA bioanalytical method validation guideline. In addition, as a part of drug development, in vitro metabolite identification has also been performed. A Kromasil C18 column was used in eluting the molecule chromatographically. The optimized mobile phase was composed of a mixture of acetonitrile and 10 mM ammonium formate buffer (pH 4.6) in 70:30 ratio (v/v). The response of the molecule was found to be linear over a calibration range of 0.2 μg/mL to 12 μg/mL. The inter-day and intra-day accuracy of the method ranged from 89.95% to 101.90% and 99.84% to 104.08%, respectively. On the other hand, the precision (%CV) value for inter-day was in between 3.50% to 6.91% and for intra-day, it was 2.11% to 8.03%. The mean recovery of the molecule at three different quality control levels was more than 85%. The analyte was stable under different stability conditions including 12 h autosampler, 8 h bench top, 15 days long term at −20 °C and three freeze-thaw cycles. The method was applied to determine stability of the molecule in human plasma. The molecule was found to be stable with more than 90% remaining even after 120 min of incubation in plasma. Two metabolites each in rat liver microsome and human liver microsome has been identified.

Erucamide from Radish Leaves Has an Inhibitory Effect Against Acetylcholinesterase and Prevents Memory Deficit Induced by Trimethyltin.

In this study, we investigated a potent acetylcholinesterase inhibitor that was isolated from radish leaf (Raphanus sativus L.) extracts. Through sequential fractionation of radish leaf extract, the active constituent was identified as cis-13-docosenamide (erucamide). To validate the potency, erucamide derived from radish leaves was supplemented in diets and then fed to trimethyltin (TMT)-exposed mice. Specifically, mice had free access to a control diet or diets containing different concentrations of erucamide for 3 weeks, followed by an injection of TMT (2.5 mg/kg body weight). Our results showed that pretreatment of mice with erucamide (20 and 40 mg/kg body weight per day) significantly attenuated the TMT-induced learning and memory deficits that were assessed by Y-maze and passive avoidance tests. These findings suggest that radish leaves, and possibly its isolated erucamide, may have preventive effects against memory deficits related to Alzheimer's disease by modulation of cholinergic functions.

UV-C light irradiation enhances toxic effects of chlorpyrifos and its formulations

UV-C irradiation is widely used in the food industry. However, the health effects from dietary exposure to the irradiated pesticide residues retained in foodstuffs are underestimated. In this study, technical chlorpyrifos (TCPF) and its oil in water (EW) and emulsifiable concentrate (EC) formulations were irradiated by UV-C, and their photodegradation products were subjected to toxicity assessment, including determination of acetylcholinesterase (AChE) activity, genotoxicity and oxidative stress using human blood cells as a model system. Toxicity studies were performed using the chlorpyrifos concentrations in the range of those proposed as the maximum residue levels in plant commodities. TCPF, EW and EC photodegradation products induced DNA damage and oxidative stress, and their genotoxicity did not decrease as a function of irradiation time. Irradiated TCPF and EC are more potent AChE inhibitors than irradiated EW. Accordingly, the application of UV-C irradiation must be considered when processing the plants previously treated with chlorpyrifos formulations.

Synthesis, enzyme inhibitory kinetics mechanism and computational study of N-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides as novel therapeutic agents for Alzheimer's disease.

The present study comprises the synthesis of a new series of sulfonamides derived from 4-methoxyphenethylamine (1). The synthesis was initiated by the reaction of 1 with 4-methylbenzenesulfonyl chloride (2) in aqueous sodium carbonate solution at pH 9 to yield N-(4-methoxyphenethyl)-4-methylbenzensulfonamide (3).This parent molecule 3 was subsequently treated with various alkyl/aralkyl halides, (4a–j), using N,N-dimethylformamide (DMF) as solvent and LiH as activator to produce a series of new N-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides (5a–j). The structural characterization of these derivatives was carried out by spectroscopic techniques like IR, 1H-NMR, and 13C-NMR. The elemental analysis data was also coherent with spectral data of these molecules. The inhibitory effects on acetylcholinesterase and DPPH were evaluated and it was observed that N-(4-Methoxyphenethyl)-4-methyl-N-(2-propyl)benzensulfonamide (5c) showed acetylcholinesterase inhibitory activity 0.075 ± 0.001 (IC50 0.075 ± 0.001 µM) comparable to Neostigmine methylsulfate (IC50 2.038 ± 0.039 µM).The docking studies of synthesized ligands 5a–j were also carried out against acetylcholinesterase (PDBID 4PQE) to compare the binding affinities with IC50 values. The kinetic mechanism analyzed by Lineweaver-Burk plots demonstrated that compound (5c) inhibits the acetylcholinesterase competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (5c) is 2.5 µM. It was also found from kinetic analysis that derivative 5c irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound 5c may serve as lead structure for the design of more potent acetylcholinesterase inhibitors.

Design and synthesis of donepezil analogues as dual AChE and BACE-1 inhibitors

Multi-target-directed ligands (MTDLs) centered on β-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4–6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC50 value of 4.11 nM) and BACE-1 inhibition (IC50 value of 18.3 nM) in comparison to donepezil (IC50 values of 6.21 and 194 nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood–brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease.

Synthesis, structure-activity relationship and molecular docking studies of 3-O-flavonol glycosides as cholinesterase inhibitors

The prime objective of this research work is to prepare readily soluble synthetic analogues of naturally occurring 3-O-flavonol glycosides and then investigate the influence of various substituents on biological properties of synthetic compounds. In this context, a series of varyingly substituted 3-O-flavonol glycosides have been designed, synthesized and characterized efficiently. The structures of synthetic molecules were unambiguously corroborated by IR, 1H, 13C NMR and ESI-MS spectroscopic techniques. The structure of compound 22 was also analyzed by X-ray diffraction analysis. All the synthetic compounds (21–30) were evaluated for in vitro inhibitory potential against cholinesterase enzymes. The results displayed that most of the derivatives were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with varying degree of IC50 values. The experimental results were further encouraged by molecular docking studies in order to explore their binding behavior with the active pocket of AChE and BChE enzymes. The experimental and theoretical results are in parallel with one another.

Synthesis, quantum chemical, in vitro acetyl cholinesterase inhibition and molecular docking studies of four new coumarin based pyrazolylthiazole nuclei

Four new 3-(2-(3-Phenyl-5-substituted phenyl-4,5-dihydropyrazol-1-yl)thiazol-4-yl)-2H-chromen-2-one derivatives (1–4) were synthesized and fully characterized by spectroscopic techniques. The final structures of all chromenone analogues (1–4) were confirmed by single crystal X-ray diffraction analysis. Quantum chemical studies were performed to compare the results from the theoretical studies with the experimental (X-ray as well as spectroscopic) ones. The theoretically simulated geometric parameters and other spectroscopic properties agreed nicely with the experimental data. All compounds were evaluated for biological activity (acetyl cholinesterase inhibition potential). Compound 3 emerged as the most potent derivative in acetylcholine esterase (AChE) inhibition assay with IC50 = 27.29 μM. The IC50 of compound 3 is greater than the standard drug galantamine (IC50 = 44.02 μM). To rationalize the potencies, molecular docking studies were also carried out. These docking results revealed a good correlation between binding energies values and in vitro AChE inhibition assay.