Potent Acetylcholinesterase Inhibitors Research Articles

Design, Synthesis and Bioevaluation of Two Series of 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines.

Two series of 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-ones and N-(1-benzylpiperidin-4-yl)quinazolin-4-amines were designed initially as potential acetylcholine esterase inhibitors. Biological evaluation demonstrated that N-(1-benzylpiperidin-4-yl)quinazolin-4-amines significantly inhibited AChE activity. Especially, two compounds of them were found to be the most potent with relative AChE inhibition percentages of 87 % in comparison to donepezil. The docking studies with AChE showed similar interactions between donepezil and four derivatives. N-(1-Benzylpiperidin-4-yl)quinazolin-4-amines also exhibited significant DPPH scavenging effects. The two series of compound also exerted moderate to good cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC-3 (prostate cancer), and NCI-H23 (lung cancer), with 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one being the most cytotoxic agent. 3-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one significantly induced early apoptosis and arrested the SW620 cells at G2/M phase. From this study, two compounds of N-(1-benzylpiperidin-4-yl)quinazolin-4-amines could serve as new leads for further design and AChE inhibitors, while 3-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]quinazolin-4(3H)-one could serve as a new lead for the design and development of more potent anticancer agents.

Floral extracts-mediated green synthesis of NiO nanoparticles and their diverse pharmacological evaluations

Biosynthesis has emerged as an exciting interface for assembling multifunctional metal oxide nanoparticles for diverse medicinal applications. Herein, biogenic nickel oxide (NiO-NPs) is synthesized by using floral extracts of Callistemon viminalis (C. viminalis) as a low cost, ecofriendly reducing and stabilizing agent. NiO-NPs were annealed at 300 °C, 400 °C and 500 °C while their physiochemical properties were established by HR-SEM/TEM, UV, XRD, FTIR, EDS, SAED and SQUID techniques. Particle size of NiO-NPs decreased with increase in annealing temperatures. Magnetization curves indicated superparamagnetic behavior of the biogenic NiO-NPs at 300 K. Highly crystalline NiO-NPs obtained after annealing at 500 °C were used for biomedical applications. The anti-leishmanial activity on Leishmania tropica promastigotes (KMH-23) and anticancer activity on HepG2 (RCB1648) revealed excellent inhibition potential with IC50 of 37.21 µg/mL and 47 µg/mL, respectively. Significant antibacterial effect was observed against Klebsiella pneumonia and Proteus vulgaris with MIC’s of 12.5 µg/mL each. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and α-glucosidase inhibitory potential were comparable with positive control drugs. Moderate antioxidant activities were observed. NiO-NPs were observed to be hemolytic (30%) at higher dose (1000 µg/mL). Overall, NiO-NPs revealed a multifunctional nature that can be explored for diverse biomedical applications. Communicated by Ramaswamy H. Sarma

Structure-Based Design and Molecular Dynamics Simulations of Pentapeptide AEYTR as a Potential Acetylcholinesterase Inhibitor

Structure-based virtual screening protocol to identify potent acetylcholinesterase inhibitors was retrospectively validated. The protocol could be employed to examine the potential of designed compounds as novel acetylcholinesterase inhibitors. In a research project designing short peptides as acetylcholinesterase inhibitors, peptide AEYTR emerged as one of the potential inhibitors. This article presents the design of AEYTR assisted by the validated protocol and guided by literature reviews followed by molecular dynamics studies to examine the interactions of the pentapeptide in the binding pocket of the acetylcholinesterase enzyme. The molecular dynamics simulations were performed using YASARA Structure in Google Cloud Platform. The peptide AEYTR was identified in silico as a potent acetylcholinesterase inhibitor with the average free energy of binding (DG) of -19.138 kcal/mol.

Dual Action of Dipyridothiazine and Quinobenzothiazine Derivatives-Anticancer and Cholinesterase-Inhibiting Activity.

The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with IC50 values from 0.78 to 19.32 μM, while their IC50 values against eqBuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an IC50 value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives.

Theoretical studies and NMR assay of coumarins and neoflavanones derivatives as potential inhibitors of acetylcholinesterase

Currently Alzheimer's disease (AD) is a devastating neurological disorder that mainly affects the elderly. The treatment of AD has as main objective to increase the levels of ACh in the synaptic cleft by inhibiting the cholinesterase enzymes, which are responsible for the degradation of ACh. Twenty one synthesized coumarins and neoflavanones (4-arylcoumarins) and theoretical studies were used to select the most promising ligands for in vitro experimental studies by Nuclear Magnetic Resonance. The eight compounds selected for the experimental study only 12b (effectiveness 68.54 ± 3.22%) was promising AChE inhibitor. This compound (12b) presents substituents at positions 4, 5, 6, 7 and 8 in a coumarin nucleus, being the most significant characteristic in comparison to the other studied compounds. These results can be used for the design and synthesis of other possible derivatives with inhibitory potential of AChE.

Novel Class of Chalcone Oxime Ethers as Potent Monoamine Oxidase-B and Acetylcholinesterase Inhibitors.

Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except COE-17 and COE-24, had potent and/or significant selective inhibitory effects on MAO-B. COE-6 potently inhibited MAO-B with an IC50 value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. COE-7, and COE-22 were also active against MAO-B, both had an IC50 value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. COE-13 most potently inhibited MAO-A (IC50 = 0.88 µM) and also significantly inhibited MAO-B (IC50 = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. COE-19 and COE-22 inhibited AChE with IC50 values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of COE-22 for MAO-B was higher than that of COE-6 (SI = 778.6 vs. 222.2), but the IC50 value (0.028 µM) was slightly lower than that of COE-6 (0.018 µM). In reversibility experiments, inhibitions of MAO-B by COE-6 and COE-22 were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with Ki values of 0.0075 and 0.010 µM, respectively. Our results show that COE-6 and COE-22 are potent, selective MAO-B inhibitors, and COE-22 is a candidate of dual-targeting molecule for MAO-B and AChE.

Chemical composition and acetylcholinesterase inhibitory potential, in silico, of Myrciaria floribunda (H. West ex Willd.) O. Berg fruit peel essential oil

Essential oils (EOs) are volatile compounds obtained from aromatic plants that can act as modulators of neurological systems. Several neurodegenerative diseases have been correlated with changes in the cholinergic system. Myrciaria floribunda (H. West ex Willd.) O. Berg (Myrtaceae) was chosen to investigate its biological potential for treating neurodegenerative diseases. M. floribunda fruit peel essential oil (MfEO) was collected for analysis. In this study, the chemical composition and in silico acetylcholinesterase inhibitory activities were determined. The results revealed the presence of 26 (96.86%) compounds obtained for GC/MS, of which the major compounds were the following: δ-Cadinene (26.8%), γ-Cadinene (15.69%), γ-Muurolene (6.21%), α-Selinene, α-Muurolene (6.11%) and (E)-Caryophyllene (5.54%). The ADMET analysis showed that MfEO compounds have a predicted lethal dose 628 times higher than neostigmine. The molecular docking results between the major components of MfEO and the enzyme acetylcholinesterase resulted in an average energy minimization of –6.6 Kcal/mol when the two structures coupled. In the assay of acetylcholinesterase activity, M. floribunda fruit peel oil presented an IC50 of 0.08 μg/ml and 23 μg/ml for commercial AChE of E. electricus and that extracted from C. rhizophorae, respectively. MfEO showed enzymatic inhibition and other relevant information of bioactive compounds. This study provides the first report of the chemical composition of the fruit peel essential oil of M. floribunda and highlights the promising results obtained through in silico analysis and the inhibitory potential of AChE through an in vitro assay.

Sulfonamides incorporating ketene N,S-acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors.

In this study, 15 novel compounds in a series of sulfonamide-based ketenes (7a-o) were synthesized and characterized using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. All compounds were tested for their ability to inhibit the human carbonic anhydrase (hCA) isoforms I and II, and acetylcholinesterase (AChE). The halogen-appended compounds, 7g, 7o, and 7i, exhibited the highest hCA I/II and AChE inhibition, with the KI values in the low nanomolar range (KI = 9.01 ± 0.08, 7.41 ± 0.03, and 7.37 ± 0.31 nM, respectively), as compared with their corresponding parent 2-[2,2-dicyano-1-(phenylamino)vinylthio]-N-(4-sulfamoylphenyl)acetamide analogs 7a-o. Besides, derivatives 7c and 7e selectively inhibited the isoform hCA I, whereas compounds 7m and 7n selectively inhibited isoform hCA II. These findings indicated that all compounds can inhibit metabolic dysfunctions, such as edema, epilepsy, glaucoma, and Alzheimer's disease, by specifically targeting both the hCA isoforms and AChE expression. Herein, also the interactions between ligands and receptors were highlighted through in silico molecular docking studies. The molecular mechanics-generalized Born surface area method was utilized to compute the binding free energy and the energy contribution of the critical residues in the active site was estimated. All these results would help us to perfectly understand the relationship between activity and structural characteristics of derivatives and to further improve newly and highly effective analogs targeting hCA and AChE.

Arylaminopropanone Derivatives as Potential Cholinesterase Inhibitors: Synthesis, Docking Study and Biological Evaluation

Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1–16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays were performed; the results are expressed as a percentage of inhibition and the IC50 values. The inhibitory activities were compared with reference drugs galantamine and rivastigmine showing piperidine derivatives (1–3) as the most potent. A possible mechanism of action for these compounds was determined from a molecular modelling study by using combined techniques of docking, molecular dynamics simulations and quantum mechanics calculations.

Ligand fishing and identification of acetylcholinesterase inhibitors in Mahonia bealei (Fort.) Carr. using high performance liquid chromatography-mass spectrometry

A fishing platform was developed using immobilized capillary enzyme reactors in combination with liquid chromatography-mass spectrometry (LC-MS) to fish acetylcholinesterase inhibitor (AChEI) from Mahonia bealei (Fort.) Carr. (M. bealei) extract. Four potential AChEIs (columbamine, jatrorrhizine, berberine, and palmatine) were successfully screened out and identified. Their AChE inhibitory activities were further verified by an in vitro assay with IC50 values of 0.93 ± 0.12 μg/mL (columbamine), 3.50 ± 0.15 μg/mL (jatrorrhizine), 2.51 ± 0.12 μg/mL (berberine), and 1.52 ± 0.13 μg/mL (palmatine). A synergy study of these AChEIs was subsequently investigated. In comparison with the IC50 value of M. bealei extract (IC50=0.83 ± 0.21 μg/mL), it can be stated that M. bealei extract is much more active than any single AChEI. Thereafter, the determination of these four alkaloids were investigated and AChE inhibitory effect were compared in terms of the extract and corresponding contents of these four alkaloids. The inhibitory effects of extract at each concentration were stronger than four alkaloids mixture. The results demonstrated that not the four AChEI mixture cause the synergistic effect but rather than the concentrations or ratios of these AChEIs play a vital role in their synergy study.

Detection of organophosphorus pesticides with liquid crystals supported on the surface deposited with polyoxometalate-based acetylcholinesterase-responsive supramolecular spheres

Here, we demonstrate use of acetylcholinesterase (AChE)-responsive polyoxometalate (POM)/surfactant supramolecular spheres to build a liquid crystal (LC)-based sensing platform for detection of organophosphorus pesticides. The self-assembled spheres are composed of hybrid materials of a POM, sodium dodecatungstophosphate (PW12), and a surfactant, myristoylcholine (Myr). It displays dark appearance when the aqueous solution is in contact with LCs supported on the octadecyltrichlorosilane-treated glass deposited with the supramolecular spheres, suggesting perpendicular orientation of LCs at the aqueous/LC interface. In contrast, LCs show bright appearance when the surface-deposited supramolecular spheres are enzymatically hydrolyzed by AChE, corresponding to planar orientation of LCs at the aqueous/LC interface. Detection of organophosphates are successfully achieved as they are potent inhibitors of AChE. The detection limit of the sensing platform reached 0.9 ng/mL for dimethoate. This method can avoid disturbance of external interference with excellent specificity and sensitivity, which makes it very promise in detection of organophosphorus pesticides.

Efficient palladium‐catalyzed C‐S cross‐coupling reaction of benzo‐2,1,3‐thiadiazole at C‐5‐position: A potential class of AChE inhibitors

Functionalization of 2,1,3‐benzothiadiazole (BTD) with thiols at C‐5 position remains low explored. Moreover, the arylthiol‐substitutions at this position are also unexplored and can not be found by a SN2 or SN1 reaction. In this sense, herein we present a new palladium‐catalyzed methodology for a wide variety of unpublished 5‐arylsulfanyl‐benzo‐2,1,3‐thiadiazole derivatives synthesis with moderate to high yields using a low catalytic loading of Pd(L‐Pro)2 as low‐coast, and efficient catalyst in low reaction time. Besides, we concluded that the pKa of thiol species has an important role in this catalysis, mainly in the CMD like catalytic cyclo process, which strongly interferes in the reaction yields. Furthermore, arylsulfanyl‐benzo‐2,1,3‐thiadiazoles derivatives have been assessed (in vitro) as potential acetylcholinesterase inhibitors.

Synthesis, biological evaluation, theoretical investigations, docking study and ADME parameters of some 1,4-bisphenylhydrazone derivatives as potent antioxidant agents and acetylcholinesterase inhibitors.

Five 1,4-bisphenylhydrazone derivatives (1-5) were successfully synthesized and evaluated for their antioxidant and acetylcholinesterase inhibitory activities. The antioxidant activity has been carried out using DPPH, ABTS, CUPRAC and superoxide radical scavenging methods. All the compounds showed a very good antioxidant activity compared to that of the standards used. Compound 1 was found to be the best antioxidant agent with IC50 values lower or comparable to that of the standards. The acetylcholinesterase inhibitory activity has been evaluated using a modified Ellman's assay. The obtained results indicate that compound 2 is the best acetylcholinesterase inhibitor with a low IC50 value comparable to that of the galantamine. In addition, DFT calculations have been performed to determine in which mechanism the synthesized hydrazones follow to scavenge free radicals. Molecular docking study was performed for compound 2, and its interaction modes with the enzyme acetylcholinesterase were determined. As a result, a strong interaction between this compound and the active site of AChE enzyme was revealed. Finally, ADME properties of the synthesized compounds were also studied and showed good drug-like properties.

Design, synthesis and evaluation of new chromone-derived aminophosphonates as potential acetylcholinesterase inhibitor.

A series of novel N-substituted α-aminophosphonates-bearing chromone moiety were synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities and antioxidant properties. Porcine pancreatic lipase was employed as a catalyst. Inhibitory activity against AChE ranged between 0.103 and 5.781µM, whereas for BuChE, activities ranged between 8.619 and 18.789µM. The results show that among the various synthesized compounds, strongest AChE inhibition was found for the compound containing aliphatic amine analogs, while in case of BuChE, aromatic amines showed better activity as compared to aliphatic amines. Compound 4j was found to be the most potent inhibitor of AChE with an IC50 value of 0.103 ± 0.24μM and inhibited AChE through mixed-type inhibition. Compound 4j was twofolds more potent than tacrine, 35-folds potent than galantamine and 50-folds potent than rivastigmine. Also, docking study revealed that compound 4j binds to both the peripheral anionic site and catalytic anionic site of AChE and BuChE. The antioxidant activities of synthesized compounds were performed against 2,2-diphenyl-1-picrylhydrazyl and hydrogen peroxide scavenging. DNA nicking activity of selected compounds also suggested that the compounds do not harm plasmid DNA pBR322. Compound 4j also showed significant DNA damage protection activity. Novel N-substituted α-aminophosphonates bearing chromone moiety were synthesized and evaluated for anti-acetylcholinesterase, anti-butyrylcholinesterase, antioxidant and DNA damage activities.

SAR based in-vitro anticholinesterase and molecular docking studies of nitrogenous progesterone derivatives

Progesterone is a steroidal hormone that has been described with pathogenic features of brain dysfunction, realized with advanced age-related neurodegenerative diseases such as Alzheimer’s disease. In this study, sixteen nitrogenous derivatives of progesterone which we previously synthesized have been used for Alzheimer targets. The progesterone derivatives (1–16) were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potentials in a dose-dependent manner. All the compounds exhibited overwhelming AChE inhibitions, with IC50 values ranging from 14.40 to 40.37 μM. Similarly, the BChE inhibitory potentials of our compounds were also dominant with IC50values between 20.08 and 46.84 μM. In comparison to our compounds, the standard drug galantamine attain IC50 values of 12.03 and 18.20 μM against AChE and BChE respectively. Molecular docking studies suggested that the compounds exerted their inhibitory activity by binding to the active site of the enzyme. The cholinergic system plays an important role in the regulation of learning and memory processes and has been a major target for the design of anti-Alzheimer’s drugs. Therefore, these nitrogen-containing progesterone derivatives will be of potential interest to researchers working in AD for developing new drugs or chemical tools to study the disease.

Pharmacokinetic Evaluation of Brain Penetrating Morpholine-3-hydroxy-2-pyridine Oxime as an Antidote for Nerve Agent Poisoning.

Nerve agents, the deadliest chemical warfare agents, are potent inhibitors of acetylcholinesterase (AChE) and cause rapid cholinergic crisis with serious symptoms of poisoning. Oxime reactivators of AChE are used in medical practice in the treatment of nerve agent poisoning, but the search for novel improved reactivators with central activity is an ongoing pursuit. For numerous oximes synthesized, in vitro reactivation is a standard approach in biological evaluation with little attention given to the pharmacokinetic properties of the compounds. This study reports a comprehensive physicochemical, pharmacokinetic, and safety profiling of five lipophilic 3-hydroxy-2-pyridine aldoximes, which were recently shown to be potent AChE reactivators with a potential to be centrally active. The oxime JR595 was singled out as highly metabolically stable in human liver microsomes, noncytotoxic oxime for SH-SY5Y neuroblastoma and 1321N1 astrocytoma cell lines, and its pharmacokinetic profile was determined after intramuscular administration in mice. JR595 was rapidly absorbed into blood after 15 min with simultaneous distribution to the brain at up to about 40% of its blood concentration; however, it was eliminated from both the brain and blood within an hour. In addition, the MDCKII-MDR1 cell line assay showed that oxime JR595 was not a P-glycoprotein efflux pump substrate. Finally, the preliminary antidotal study against multiple LD50 doses of VX and sarin in mice showed the potential of JR595 to provide desirable therapeutic outcomes with future improvements in its circulation time.

Extraction and isolation of acetylcholinesterase inhibitors from Citrus limon peel using an in vitro method.

A simple and efficient ultrafiltration-liquid chromatography-mass spectrometry-based method was developed for the rapid screening and identification of ligands from Citrus limon peel, which are suitable acetylcholinesterase inhibitors. Subsequently, the anti-Alzheimer's activity of these compounds was assessed using a PC12 cell model. Six major compounds, viz. neoeriocitrin, isonaringin, naringin, hesperidin, neohesperidin, and limonin, were identified as potent acetylcholinesterase inhibitors. A continuous and efficient online method, which involved the use of a microwave-assisted extraction device, solvent concentration tank, and centrifugal partition chromatography column, was developed for the scale-up of these compounds, and the obtained compounds presented high purity. Next, their bioactivity was evaluated using a PC12 cell model. This novel approach, which was based on ultrafiltration-liquid chromatography-mass spectrometry, microwave-assisted extraction online coupled with solvent concentration tank, and centrifugal partition chromatography along with in vitro evaluation, could represent a powerful tool for the screening and extraction of acetylcholinesterase inhibitors from complex matrices, and could be a useful platform for the large-scale production of bioactive and nutraceutical ingredients.

Aporphinoid Alkaloids Derivatives as Selective Cholinesterases Inhibitors: Biological Evaluation and Docking Study.

Alzheimer's dementia is a neurodegenerative disease that affects the elderly population and causes memory impairment and cognitive deficit. Manifestation of this disease is associated to acetylcholine decrease; thus, Cholinesterase inhibition is the main therapeutic strategy for the treatment of Alzheimer's disease. In the present study, a series of aporphinoid alkaloids were tested as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors in vitro. Alkaloids liriodenine (3) and cassythicine (10) were the best inhibitors of both cholinesterases with IC50 values lower than 10 μM. In addition, these alkaloids demonstrated better inhibition of BChE than reference drug galantamine. In addition, some alkaloids showed selective inhibition. Laurotetatine clorhydrate (13) selectively inhibit AChE over BChE. On the contrary, pachyconfine (7) interacted more efficiently with BChE active site. Molecular modelling studies were performed in order to illustrate key interactions between most active compounds and the enzymes and to explain their selectivity. These studies reveal that the benzodioxole moiety exhibits strong interactions due to hydrogen bonds that form with the Glu201 (AChE) and Tyr440 (BChE) residues, which is reflected in the IC50 values.

Organocatalyzed Solvent Free and Efficient Synthesis of 2,4,5-Trisubstituted Imidazoles as Potential Acetylcholinesterase Inhibitors for Alzheimer's Disease.

The catalytic potential of pyridine-2-carboxlic acid has been evaluated for efficient, green and solvent free synthesis of 2,4,5-trisubstituted imidazole derivatives 3a-3m. The compounds 3a-3m were synthesized by one pot condensation reaction of substituted aromatic aldehydes, benzil, and ammonium acetate in good to excellent yields (74-96 %). To explore the potential of these compounds against Alzheimer's disease, their inhibitory activities against acetylcholinesterase (AChE) were evaluated. In this series of compounds, compound 3m, bearing one ethoxy and a hydroxy group on the phenyl ring on 2,4,5-trisubstituted imidazoles, proved to be a potent AChE inhibitor (102.56±0.14). Structure-activity relationship (SAR) of these compounds was developed. Molecular dockings were carried out for the compounds 3m, 3e, 3k, 3c, 3a, 3d, 3j, and 3f in order to further investigate the binding mechanism. The inhibitor molecule was molecularly docked with acetylcholinesterase to further study its binding mechanism. The amino group of the compound 3m forms an H-bond with the oxygen atom of the residue (i. e., THR121) which has a bond length of 3.051 Å.

Characterization of phenolic profile by LC-ESI-MS/MS and enzyme inhibitory activities of two wild edible garlic: Allium nigrum L. and Allium subhirsutum L.

In our study, Allium nigrum L. and Allium subhirsutum L. were investigated in terms of phenolic profile, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and tyrosinase inhibitory potentials. The colorimetric analysis revealed that the highest levels of total phenol (45.6, 15.8mg GAE/g extract, respectively) and total flavonoid contents (8.2, 5.7mg QE/g extract, respectively) were found in the bulbs of both plants. About 30 compounds were determined by LC-ESI-MS/MS with validated method and 3-hydroxybenzoic acid (2,188.4μg/g extract) and p-coumaric acid (1,700.8μg/g extract) were major phenolic acids. (-)-Epigallocatechin gallate (998.3µg/g extract) and genistein (159.3μg/g extract) which are neuroprotective compounds were the predominant flavonoids for A. nigrum and A. subhirsutum, respectively. Enzyme inhibitory activities of samples were performed by spectrophotometrically with 96-well microplate reader. All samples showed anti-AChE, anti-BuChE, and anti-tyrosinase activities and the aerial part of A. nigrum was the most potent (IC50 6.1, 3.27, 22.31µg/ml, respectively). PRACTICAL APPLICATIONS: Many Allium species, especially those cultivated, are consumed in different countries as food in different ways. In the literature, studies on these species have generally focused on organosulfur compounds of the species. In our present study, phenolic compounds having a wide range of biological activities were determined in different parts of the two Allium species consumed as food. We also investigated in vitro cholinesterases and tyrosinase inhibition activities of these species. A correlation was observed between phenolic compounds and enzyme inhibition activities. These results were further explored and confirmed by principal component analysis (PCA). PCA revealed that samples were discriminated from each other according to phenolic compounds and enzyme inhibitory potencies. Conclusively, this study determines that the chemical profiles and biological activities of A. nigrum and A. subhirsutum.