Synthesis,antioxidant and anticholinesterase activities of novel quinoline-aminophosphonate derivatives

A series of 20 novel α-aminophosphonate derivatives bearing quinoline or quinolone moiety was designed and synthesized via Kabachnik-Fields reaction in the presence of triethylammonium acetate as a solvent and catalyst under ultrasound irradiation. This procedure affords products in high yields and short reaction times. Molecular structures of the synthesized compounds 4a-g and 5a-m were confirmed using various spectroscopic methods. The antioxidant activity of these compounds was evaluated by eight complementary in vitro tests. The anticholinesterase activity (AChE, BChE) of these compounds were also evaluated. In addition, theoretical calculations of all compounds were investigated as corrosion inhibitors using density functional theory (DFT). The results revealed that 16 of these compounds exhibited high levels of antioxidant activities depending on the assay and that most compounds showed more potent inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).     

基于固定化酶的乙酰胆碱酯酶抑制剂体外筛选模型的建立

以可重复使用的固定化酶代替游离态酶, 建立一种基于比色分析的乙酰胆碱酯酶(AChE)抑制剂体外筛选新模型. 采用以氨基化硅胶为载体固定的AChE优化了实验条件, 用AChE抑制剂阳性对照物他克林和毒扁豆碱对该模型进行验证, 还对模型技术参数进行评价, 并将新模型用于单体化合物及天然产物粗提物AChE抑制活性评价. 结果表明, 最佳实验条件为: 固定化酶用量55 μL, 底物浓度5 mmol/L, 甲醇、 乙醇及体积分数不高于6%的二甲基亚砜水溶液均可作为样品溶剂; 模型验证及模型技术参数评价结果良好, 该模型对AChE抑制剂筛选有较好的特异性和灵敏度, 可用于筛选AChE抑制剂. 该模型具有适用性强、 固定化酶可重复使用及结果可靠等优点, 是单体化合物及天然产物粗提物AChE抑制剂活性评价的有效方法.     

Effect of Ultraviolet Radiation on Acetylcholinesterase Activity in Freshwater Copepods

We analyzed the effects of UV radiation (UVR) effects on acetylcholinesterase (AChE) activity in two calanoid copepods, Boeckella gibbosa and Parabroteas sarsi that inhabit Patagonian shallow lakes. We studied the effect of experimental UVR (UV-B and UV-A) exposure on AChE activity in relation to basal antioxidant capacities of both copepods. Our experiments showed that UVR can effectively depress AChE activity, although with differences between species. In both copepods AChE was affected by UV-B, whereas UV-A only affected AChE in B. gibbosa. Both copepods also differed in body elemental composition (C:N:P), photoprotecting compound content (carotenoids and mycosporine-like amino acids) and enzymatic antioxidant capacity (glutathione S-transferase [GST]). Our results suggest that when exposed to UVR, AChE activity would depend more on the antioxidant capacity (GST) and P availability for enzyme synthesis than on the photoprotective compounds.     

Ultrasound-assisted synthesis of benzothiazepines and assessment of their in vitro acetylcholinesterase inhibition activity

A series of steroidal 1,5-benzothiazepine and its derivatives have been synthesized by the reaction of α,β-unsaturated ketones with 2-aminothiophenol using small amount of dimethylformamide (DMF) as a solvent and catalytic amount of acetic acid at 45–50°C under ultrasonic irradiation. This method provides several advantages such as the shortest reaction time, high yields, simple work-up procedure, and purification of products by nonchromatographic methods. All the synthesized compounds were screened for their acetylcholinesterase (AChE) inhibition activity. These compounds exhibited moderate AChE inhibition activity as compared to the standard drug, tacrine. Compound 5 showed the highest inhibition among all benzothiazepines. The AChE inhibition activity of the compound 5 was further investigated with the help of in silico docking study to predict the active sites.     

Dual inhibitors of Interleukin-6 and acetylcholinesterase for treatment of Alzheimer's disease: Design,docking, synthesis and biological evaluation

Multitarget compounds intercept two or more functionally complementary pathways simultaneously, and are therefore considered to have potential in effectively treating complex multifactorial diseases like Alzheimer's disease (AD). In the present study, novel molecules are designed by coupling a chromone and a N,N-disubstituted carbamoyl amine as pharmacophore for interleukin-6 (IL-6) and acetylcholinesterase (AChE) inhibition, respectively. Four series (Y1–Y4) of 40 compounds are designed by using alkyl linkers of different lengths (1–4 carbon atoms) for the coupling of the two selected pharmacophore. Docking of all designed compounds in AChE leads to the identification of twelve best fit compounds (Docking score >8.3). The data suggests that a 1- or 2-carbon atom linker is the most conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 12 selected compounds suggest that these can cross the blood brain barrier (BBB) with good oral bioavailability. These compounds are synthesised and evaluated for anti-AChE activity. Five compounds, showing >45% inhibition of AChE, are further evaluated for IL-6 inhibitory activity. Compound Y1f is found to be the most potent inhibitor of both AChE and IL-6 (IC₅₀ 0.7 and 0.8 ​μM, respectively). It suggests that a chromone moiety connected to a piperidine ring through a 1-carbon atom linker may provide a useful template to medical chemists for the development of new chemical entities effective against AD.     

QSAR for Acetylcholinesterase Inhibition and Toxicity of Two Classes of Phosphoramidothioates

Abstract

Methamidophos (Met) is a weak inhibitor of housefly head AChE but at the same time it is highly toxic to the common housefly. The lethality of Met is believed to be due to AChE inhibition. An extensive QSAR study may help in determining the mode of action of Met in vivo and in vitro and provide a rational for its high insecticidal toxicity. Acephate (Ace), like Met, is a poor inhibitor of AChE in vitro and has a comparable to Met insect toxicity in vivo. Contrary to Met, though, Ace has much lower mammalian toxicity. Understanding the structural properties which make insecticides toxic to insects but not to mammals is of great importance, since mammals (including humans) are inadvertently exposed to these compounds.

Our results were consistent with the model in which both the in vitro and in vivo toxicity of Met depends on the inhibition of the active center of AChE by the unchanged Met. An optimal susceptibility to hydrolysis is needed for Met and its analogs to have high insecticidal activity since in order to phosphorylate AChE they need to be hydrolyzed and at the same time their stability is of great importance in vivo for accumulating at the site of action. The insecticidal activity of Ace analogs may be due to direct interaction with the active center of the AChE. The mammalian toxicity of Ace analogs may be due to interaction with an 'allosteric' reaction center in the AChE.     

Synthesis of 1H,7H,12bH‐Pyrano[3′,4′: 5,6]pyrano[3,4‐c][1]benzopyran‐1‐one via Domino Knoevenagel/Hetero‐Diels?Alder Reaction with Theoretical Investigations

The CuI‐catalyzed intramolecular oxa‐Diels? Alder reaction of 2‐(prop‐2‐yn‐1‐yloxy)benzaldehydes as unactivated terminal alkynes with 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one is described. The reaction proceeds with remarkable chemoselectivity to yield pyranones 3 (Scheme 1). A theoretical investigation of the reaction in terms of HOMO? LUMO interactions in the gas phase is also reported. The reaction could be regarded as an inverse‐electron‐demand Diels? Alder cycloaddition. The theoretical results are in high agreement with the experimental evidences.     

Chemical constituents,Antibacterial and Acetylcholine esterase inhibitory activity of Cupressus macrocarpa leaves

Abstract

The chemical constituents of Cupressus macrocarpa were investigated. A new neolignan glycoside (1) in addition to nine known compounds were isolated. The acetylcholinesterase (AChE) inhibitory activity and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) of different fractions and isolates of C. macrocarpa were evaluated. The light petroleum fraction showed the highest activity in both assays with IC₅₀ value of 88.79 µg/ml and 152.58 µg/ml for the AChE inhibitory activity and MRSA antibacterial activities, respectively. Weak to moderate activity were detected for the isolated compounds.     

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.     

膦酰化肟对乙酰胆碱酯酶的抑制作用及中毒酶重活化特性研究——基于效应标志物质谱定量分析技术

将对氧磷(Paraoxon)与肟类重活化剂双复磷(Obidoxime)反应制得膦酰化肟(DEP-obidoxime);利用基于效应标志物的质谱定量技术研究了膦酰化肟对乙酰胆碱酯酶(AChE)的抑制作用及中毒酶的重活化特性.结果表明,膦酰化肟具有极强的AChE抑制毒性,但因膦酰化肟中毒酶与原有机磷毒物中毒酶结构相同,故其膦酰化AChE仍可被经典重活化剂[如氯解磷定(Pralidoxime)、双复磷(Obidoxime)及酰胺磷定(HI-6)]重活化,根据EC_(50)表征结果,这3种重活化剂的重活化效果强弱顺序依次为氯解磷定HI-6双复磷.     

Design,Synthesis, and Characterization of Quinoxaline Derivatives as a Potent Antimicrobial Agent

A series of quinoxalinone derivatives were synthesized by the reaction of o‐phenylenediamine with oxalic acid to yield 1, 4‐dihydro quinoxaline‐2, 3‐dione ( 1 ) and then treated with thionyl chloride to yield 2, 3 dichloro quinoxaline ( 2 ). This was further reacted with hydrazine hydrate to produce 2, 3‐dihydrazinyl quinoxaline ( 3 ). This was finally reacted with substituted aromatic aldehydes to produce 2,3‐bis[2‐(sustituted benzylidine) hydrazinyl] quinoxalines ( 4 ). These quinoxalinone derivatives were characterized by infrared spectroscopy and nuclear magnetic resonance spectroscopy and MASS spectral data. All the synthesized compounds were evaluated for their antimicrobial activity. The results of the antimicrobial study revealed that compounds 4c , 4d , and 4i were active and exhibited better inhibitory activities as compared to standard drug ciprofloxacin. The results were further checked with protein legend interaction by using docking studies, and all the compounds exhibited good docking scores between ?8.72 and ?11.29 kcal/mol against dihydrofolate reductase protein fragment from Staphylococcus aureus (PDB ID‐4XE6). Among all compound, 4c has shown maximum docking score and found in agreement to in vitro studies.     

Chemical Constituents from the Wild Atractylodes macrocephala Koidz and Acetylcholinesterase Inhibitory Activity Evaluation as Well as Molecular Docking Study

Screening the lead compounds which could interact both with PAS and CAS of acetylcholinesterase (AChE) is an important trend in finding innovative drugs for Alzheimer’s disease (AD). In this paper, four sesquiterpenes, i.e., atractylenolide III (1), atractylenolide IV (2), 3-acetyl-atractylon (3) and β-eudesmol (4), were obtained from the wild Atractylode macrocephala grown in Qimen for the first time. Their structures were elucidated mainly by NMR spectroscopy. To screen the potential dual site inhibitors of AChE, the compounds 1, 2, 3, as well as a novel and rare bisesquiterpenoid lactone, biatractylenolide II (5), which was also obtained from the tilted plant in our previous investigation, were evaluated their AChE inhibitory activities by using Ellman’s colorimetric method. The results showed that biatractylenolide II displayed moderate inhibitory activity (IC₅₀ = 19.61 ± 1.11 μg/mL) on AChE. A further molecular docking study revealed that biatractylenolide II can interact with both the peripheral anionic site (PAS) and the catalytic active site (CAS) of AChE. These data suggest that biatractylenolide II can be considered a new lead compound to research and develop more potential dual site inhibitors of AChE.     

Novel thiazole‐piperazine derivatives as potential cholinesterase inhibitors

Dementia is a cognitive disorder mostly associated with Alzheimer's disease (AD) in addition to being seen in many other diseases of the central nervous system (CNS). The limited number of drugs is not sufficient to provide adequate improvement to increase the quality of life of patients suffering from this symptom; therefore, all treatment options should be evaluated in detail. In this study, new molecules, [2‐(4‐(2/3/4‐substituted phenyl)piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted phenyl]methanone derivatives ( 1‐44 ), were obtained and analyzed in terms of their anticholinesterase activities. Kinetic mode and molecular interactions were also evaluated. An enzyme inhibition study was undertaken on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the Ellman method. Maestro program was used in molecular modeling studies. Forty‐four compounds were evaluated on AChE and BChE enzymes at 10^?3 and 10^?4 concentrations. The inhibition concentrations were calculated as 0.268μM to 2.104μM for six compounds ( 4 , 5 , 16 , 27 , 37 , and 38 ) on AChE. Compound 5 including the 4‐methoxy substituent (IC₅₀: 0.268μM) and compound 38 containing the 4‐methoxy and 3‐methyl substituents (IC₅₀: 0.286μM) showed the highest AChE inhibitory activity. They were further examined in terms of hydrogen bonding with Arg296 and Ar‐Ar interaction with Trp286. The activity of compound 5 was also assessed in mixed‐type kinetic mode.     

A novel assay to determine acetylcholinesterase activity: The application potential for screening of drugs against Alzheimer's disease

Acetycholinesterase (AChE) that regulates hydrolysis of acetylcholine (ACh) in the brain, is an important target for treatment of Alzheimer's disease (AD), a feature of which is ACh deficiency. However, the methods to precisely determine AChE activity are still under development. We developed a new method to exploit acetylcholine‐d₄ as a surrogate substrate of ACh and measure product choline‐d₄ via liquid chromatography–tandem mass spectrometry (LC–MS/MS). This assay detected activity of AChE present in the normal mouse brain, which is consistent with the standard Ellman assay that determines products spectrophotometrically. In AD mouse models, the result of LC–MS/MS assay showed significant higher AChE activity than that seen in control normal mice, while treatment of AD mice with an AChE inhibitor, huperzine A, led to partial decreases in AChE activity. Our results suggest that this surrogate‐based LC–MS/MS method is a new, sensitive and convenient assay for the determination of AChE activity, providing a useful means for screening active compounds that target AChE.     

1,3,5-Triazine Nitrogen Mustards with Different Peptide Group as Innovative Candidates for AChE and BACE1 Inhibitors

A series of new analogs of nitrogen mustards (4a–4h) containing the 1,3,5-triazine ring substituted with dipeptide residue were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and β-secretase (BACE1) enzymes. The AChE inhibitory activity studies were carried out using Ellman’s colorimetric method, and the BACE1 inhibitory activity studies were carried out using fluorescence resonance energy transfer (FRET). All compounds displayed considerable AChE and BACE1 inhibition. The most active against both AChE and BACE1 enzymes were compounds A and 4a, with an inhibitory concentration of AChE IC₅₀ = 0.051 µM; 0.055 µM and BACE1 IC₅₀ = 9.00 µM; 11.09 µM, respectively.     

Structure—activity relationships for <Emphasis Type="Italic">in vitro</Emphasis> oxime reactivation of chlorpyrifos-inhibited acetylcholinesterase

Organophosphorus pesticides parathion, chlorpyrifos, and malathion inhibit the enzyme acetylcholinesterase (AChE; EC 3.1.1.7) via phosphorylation of its active site. AChE reactivators and anticholinergics are compounds used as antidotes in the case of intoxication by these AChE inhibitors. In this work, chlorpyrifos, a representative member of this pesticide family, was used to inhibit the AChE activity of rat brain. The effect of twenty-one structurally different AChE reactivators was tested in vitro and subsequently, the relationship between their chemical structure and biological activity was outlined.     

Normal phase HPLC-based activity profiling of non-polar crude plant extracts – acetylcholinesterase inhibiting guttiferones from Montrouziera cauliflora as a case study

The study describes bioactive compounds as inhibitors of acetylcholinesterase (AChE), from the stem bark extract of Montrouziera cauliflora, selected among 19 dichloromethane extracts from Clusiaceae species. Our work focused on the development of an original normal phase HPLC microfractionation strategy to rapidly assess highly active zones from this crude active non-polar plant extract. Two different microfraction collection methods were evaluated for the assessment of the AChE inhibition. Two guttiferones and a tocotrienol were directly isolated among five compounds identified off-line by NMR after upscaling the fractionation and their AChE inhibition was evaluated. The strengths and weaknesses of the two microfractionation collection methods for HPLC-AChE activity-based profiling are discussed.     

Synthesis,antioxidant, and anticholinesterase activities of novel N-arylsulfonyl hydrazones bearing sulfonate ester scaffold

In this research, two new series of N-arylsulfonyl hydrazone compounds ( 14 – 25 ) possessing a sulfonate moiety were synthesized and characterized by elemental analysis and various spectroscopic techniques including fourier transform infrared (FT-IR), ¹H-, and ¹³C nuclear magnetic resonance (NMR). These compounds synthesized as target molecules ( 14 – 25 ) were tested for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities and antioxidant potential. The antioxidant capacities of the tested molecules were determined by four different assays. The IC₅₀ values of the screened molecules were determined in the range of 60.14 ± 0.25–84.81 ± 1.09 μM against AChE and in the range of 70.11 ± 0.67–93.60 ± 0.47 μM against BChE. In the AChE assay, 4-hydroxybenzaldehyde-based compound 25 (60.14 ± 0.25 μM) showed the highest activity in comparison to rivastigmine (501 ± 3.08 μM). This compound (71.42 ± 0.19 μM) is also one of the compounds with the highest activity against BChE. In the BChE assay, 2-hydroxybenzaldehyde-based compound 19 (70.11 ± 0.67 μM) indicated the highest activity in comparison to rivastigmine (19.95 ± 0.20 μM). In antioxidant activity studies, the tested molecules showed lower activities than the standard compounds (butylated hydroxytoluene and α-tocopherol). Consequently, some novel compounds can be used as potential inhibitor candidates in future studies.     

Synthesis and insecticidal evaluation of novel N‐oxalyl derivatives of diacylhydrazines containing methylcarbamate moieties

A series of new N‐oxalyl derivatives of diacylhydrazines containing methylcarbamate moieties were synthesized by the reaction of N‐oxalyl chloride of N‐methylcarbmates with N‐tert‐butyl‐N,N′‐diacylhydrazines in the presence of sodium hydride. The reaction of oxalyl chloride with N‐tert‐butyl‐N, N′‐diacylhydrazines to yield 1,3,4‐oxadiazole and 4‐tert‐butyl‐2‐substituted‐phenyl‐4H‐1,3,4‐oxadiazine‐5,6‐dione was found, and the reaction was studied in some detail. The title compounds were evaluated for molting hormone mimicking activity. The results of bioassay showed that the title compounds exhibit moderate larvicidal activities, and toxicity assays indicated that these compounds can induce a premature, abnormal, and lethal larval molt. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:472–475, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20135     

Acetylcholinesterase-Inhibiting Activity of Salicylanilide <em>N</em>-Alkylcarbamates and Their Molecular Docking

A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'_(3,4) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'₍₄₎ exhibited slightly more effective AChE inhibitors than in C'₍₃₎. Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain.