Anticholinesterase activity screening of some novel dithiocarbamate derivatives including piperidine and piperazine moieties

The present study was undertaken to synthesize some novel lipophilic piperazine and piperidinedithiocarbamates and investigate their inhibitory potencies against cholinesterase enzymes. In the synthetic studies, 44 new compounds were isolated. The structures of the synthesized compounds were confirmed by spectroscopic analyses. Enzymatic studies were carried out using modified Ellman's assay against Acetylcholinesterase (AChE) and Butrylcholinesterase (BChE) enzymes, and it was observed that some of the compounds selectively inhibit AChE. Theoretical ADME predictions were calculated for selected compounds in the series. Enzyme kinetics and molecular docking studies were performed for the most active compound C41 and nature of inhibition and interactions between enzyme and ligand were explained.     

2-methylindole analogs as cholinesterases and glutathione S-transferase inhibitors: Synthesis,biological evaluation,molecular docking,and pharmacokinetic studies

In this study, we aimed to (i) synthesize new 2-methylindole analogs containing various amino structures, pyrrolidine, piperidine, morpholine, and substituted phenyl groups through structural and molecular modifications, (ii) evaluate the pharmaceutical potential of 2-methylindole analogs via assessing enzyme inhibitory activity against glutathione S-transferase (GST), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), (iii) predict ADMET and pharmacokinetic properties of the synthesized 2-methylindole analogs, (iv) reveal the possible interactions between the synthesized 2-methylindole analogs with GST, AChE, and BChE enzymes using several molecular docking software. In vitro enzyme inhibition assays showed that the synthesized indole analogs exhibited moderate to good inhibitory activities against GST, AChE, and BChE enzymes. Briefly, the inhibitory activities of the analogs 4b and 4i against AChE, 4a and 4b against BChE, and analogs 1 and 4i against GST were detected to be higher or close to the standard inhibitor compounds. The analog 4b was detected to have the best inhibitory activity against both AChE and BChE enzymes with the lowest IC₅₀ values as 0.648 µM for AChE and 0.745 µM for BChE. The analyses of enzyme inhibition relationship with the synthesized analogs could help to design new analogs for the inhibitors of cholinergic and glutathione pathways based on the indole derivatives.     

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.     

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.     

Cholinesterases,carbonic anhydrase inhibitory properties and in silico studies of novel substituted benzylamines derived from dihydrochalcones

A series of novel urea, sulfamide and N,N-dipropargyl substituted benzylamines were synthesized from dihydrochalcones. The synthesized compounds were evaluated for their cholinesterases and carbonic anhydrase inhibitory actions. The known dihydrochalcones were converted into four new benzylamines via reductive amination. N,N-Dipropargylamines, ureas and sulfamides were synthesized following the reactions of benzylamines with propargyl bromide, N,N-dimethyl sulfamoyl chloride and N,N-dimethyl carbamoyl chloride. The novel substituted benzylamines derived from dihydrochalcones were evaluated against some enzymes such as human erythrocyte carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The novel substituted benzylamines derived from dihydrochalcones exhibited K_i values in the range of 0.121–1.007 nM on hCA I, and 0.077–0.487 nM on hCA II closely related to several pathological processes. On the other hand, K_i values were found in the range of 0.112–0.558 nM on AChE, 0.061–0.388 nM on BChE. As a result, novel substituted benzylamines derived from dihydrochalcones showed potent inhibitory profiles against indicated metabolic enzymes. In addition, Induced-Fit Docking (IFD) simulations and ADME prediction studies have also been carried out to elucidate the inhibition mechanisms and drug-likeness of the synthesized compounds. Therefore, these results can make significant contributions to the treatment of some global diseases, especially Alzheimer's diseases and glaucoma, and the development of new drugs.     

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).     

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.     

Novel conjugates of 4-amino-2,3-polymethylenequinolines and vanillin as potential multitarget agents for AD treatment

A series of novel conjugates of 4-amino-2,3-polymethylene quinolines and phenolic antioxidant vanillin was synthesized by the condensation of aminoquinolines with vanillin followed by reduction of imines with sodium borohydride. The conjugates effectively inhibit AChE and BChE with preferable BChE inhibition and displace propidium from the PAS AChE. Compounds with aminoalkyl spacer have preferable esterase profile being more potent cholinesterases inhibitors with lower anti-CES activity and are the most potent antioxidants in ABTS and FRAP tests.     

Synthesis of new <Emphasis Type="Italic">N</Emphasis>-(pyridin-3-ylmethyl)-2-aminothiazoline derivatives possessing anticholinesterase and antiradical activity as potential multifunctional agents for the treatment of neurodegenerative diseases

New N-(pyridin-3-ylmethyl)-2-aminothiazolines containing various substituents at the 5 position of the thiazoline ring and the 4-tert-butylbenzyl, 4-isopropylbenzyl, or 4-fluorobenzyl moiety at the nitrogen atom of the amino group were synthesized. The inhibitory activity of the synthesized compounds against human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), equine serum butyrylcholinesterase (BChE, EC 3.1.1.8), and porcine liver carboxylesterase (CaE, EC 3.1.1.1) was evaluated and their antioxidant properties were studied by ABTS assay. N-(Pyridin-3-ylmethyl)-2-aminothiazolines proveded to be very weak AChE inhibitors, while their inhibitory activity against BChE and CaE was structure-dependent. 2-Aminothiazolines containing the 4-tert-butylbenzyl moiety are more efficient BChE inhibitors compared to the derivatives containing the 4-isopropylbenzyl or 4-fluorobenzyl substituent. An analysis of the dependence of the esterase profile of N-(pyridin-3-ylmethyl)-2-aminothiazolines on the structure of the substituent at the 5 position of the thiazoline ring of these compounds demonstrated that the derivatives containing the iodomethyl substituent possess the highest anti-BChE activity, the compounds with R² = H and R³ = CH₂I have the optimal esterase profile. Regardless of the structure of the substituents in the benzyl moiety, all N-(pyridin-3-ylmethyl)-2-aminothiazolines containing the iodomethyl substituent at the 5 position of the thiazoline ring exhibited high radical scavenging activity comparable with that of the standard antioxidant Trolox. N-(Pyridin-3-ylmethyl)-2-aminothiazolines were shown to be a new promising class of compounds for the design of multifunctional agents for the treatment of neurodegenerative diseases.     

Bio-Potency and Molecular Docking Studies of Isolated Compounds from Grewia optiva J.R. Drumm. ex Burret

In the study, two novel compounds along with two new compounds were isolated from Grewia optiva. The novel compounds have never been reported in any plant source, whereas the new compounds are reported for the first time from the studied plant. The four compounds were characterized as: 5,5,7,7,11,13-hexamethyl-2-(5-methylhexyl)icosahydro-1H-cyclopenta[a]chrysen-9-ol (IX), docosanoic acid (X), methanetriol mano formate (XI) and 2,2’-(1,4-phenylene)bis(3-methylbutanoic acid (XII). The anticholinesterase, antidiabetic, and antioxidant potentials of these compounds were determined using standard protocols. All the isolated compounds exhibited a moderate-to-good degree of activity against acetylcholinesterases (AChE) and butyrylcholinesterase (BChE). However, compound XII was particularly effective with IC₅₀ of 55 μg/mL (against AChE) and 60 μg/mL (against BChE), and this inhibitory activity is supported by in silico docking studies. The same compound was also effective against DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid) radicals with IC₅₀ values of 60 and 62 μg/mL, respectively. The compound also significantly inhibited the activities of α-amylase and α-glucosidase in vitro. The IC₅₀ values for inhibition of the two enzymes were recorded as 90 and 92 μg/mL, respectively. The in vitro potentials of compound XII to treat Alzheimer’s disease (in terms of AchE and BChE inhibition), diabetes (in terms of α-amylase and α-glucosidase inhibition), and oxidative stress (in terms of free radical scavenging) suggest further in vivo investigations of the compound for assessing its efficacy, safety profile, and other parameters to proclaim the compound as a potential drug candidate.     

The design of fluoroquinolone-based cholinesterase inhibitors: Synthesis,biological evaluation and in silico docking studies

An enhanced acetylcholinesterase (AChE) activity is a hallmark in early stages of Alzheimer's ailment that results in decreased acetylcholine (ACh) levels, which in turn leads to cholinergic dysfunction and neurodegeneration. Consequently, inhibition of both AChE and butyrylcholinesterase (BChE) is important to prolong ACh activity in synapses for the enhanced cholinergic neurotransmission. In this study, a series of new fluoroquinolone derivatives (7a-m) have synthesized and evaluated for AChE and BChE inhibitory activities. The screening results suggested that 7 g bearing ortho fluorophenyl was the most active inhibitor against both AChE and BChE, exhibiting IC₅₀ values of 0.70 ± 0.10 µM and 2.20 ± 0.10 µM, respectively. The structure–activity relationship (SAR) revealed that compounds containing electronegative functions (F, Cl, OMe, N and O) at the ortho position of the phenyl group exhibited higher activities as compared to their meta- and/or para substituted counterparts. Molecular docking studies of synthesized compounds 7a, 7g, 7j and 7l docked into the active site of AChE and 7a-f docked into the active site of BChE revealed that these compounds exhibited conventional H-bonding along with π-π interaction with the active residues of AChE through their electronegative functions and phenyl ring, respectively. All the synthesized compounds are characterized by spectroscopic methods including FT-IR, ¹H- and ¹³C NMR as well as elemental analysis. This is the first example of fluoroquinolone-based cholinesterase inhibitors.     

4-N-苯胺基喹啉衍生物的合成及胆碱酯酶抑制活性

设计合成了一系列4-N-苯胺基喹啉类衍生物,采用Ellman法测定了目标化合物对乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)的抑制活性.结果表明,当喹啉环上连有伸长的吡啶季铵盐片段时,可显著提高目标化合物的胆碱酯酶抑制作用.化合物16对AChE和BChE具有明显的双重抑制作用,其IC_(50)值分别为0.92和14.20μmol/L,抑制效果强于阳性对照药加兰他敏.     

In vitro enzyme inhibition activities of crude ethanolic extracts derived from medicinal plants of Pakistan

Twenty two crude ethanolic extracts from 14 indigenous medicinal plants were subjected to enzyme inhibition screening against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase enzymes (LO). Three extracts showed activity against AChE, nine extracts were found to be active against BChE and four extracts inhibited the enzyme LO. The most significant inhibition activities (> or =50%) were found in extracts derived from Aloe vera (leaves), Alpinia galanga (rhizome), Curcuma longa (rhizome), Cymbopogon citratus (leaves), Ocimum americanum (leaves), Ocimum americanum (stem) and Withania somnifera (roots).     

Molecular docking studies and in vitro cholinesterase enzyme inhibitory activities of chemical constituents of Garcinia hombroniana

Garcinia species are reported to possess antimicrobial, anti-inflammatory, anticancer, anti-HIV and anti-Alzheimer's activities. This study aimed to investigate the in vitro cholinesterase enzyme inhibitory activities of garcihombronane C (1), garcihombronane F (2), garcihombronane I (3), garcihombronane N (4), friedelin (5), clerosterol (6), spinasterol glucoside (7) and 3β-hydroxy lup-12,20(29)-diene (8) isolated from Garcinia hombroniana, and to perform molecular docking simulation to get insight into the binding interactions of the ligands and enzymes. The cholinesterase inhibitory activities were evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. In this study, compound 4 displayed the highest concentration-dependent inhibition of both AChE and BChE. Docking studies exhibited that compound 4 binds through hydrogen bonds to amino acid residues of AChE and BChE. The calculated docking and binding energies also supported the in vitro inhibitory profiles of IC₅₀. In conclusion, garcihombronanes C, F, I and N (1–4) exhibited dual and moderate inhibitory activities against AChE and BChE.     

Novel Substituted Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives: Synthesis,Characterization, Molecular Docking Study,and Investigation of Their In Vitro Antifungal Activities

In this study, a new series of substituted imidazo[2,1‐b][1,3,4]thiadiazole derivatives were synthesized. To this end, first 2‐amino‐1,3,4‐thiadiazole derivatives (compounds 2a and 2b ), the starting materials, were synthesized with high yields (82% and 79%, respectively). Then imidazo[2,1‐b][1,3,4]thiadiazole derivatives ( 4 – 16 ), the target compounds, were synthesized from reactions of 2‐amino‐1,3,4‐thiadiazole derivatives ( 2a and 2b ) with 2‐bromoacetophenone derivatives ( 3a – 3i ) (in yields of 52% to 71%). All of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, Fourier transform infrared, elemental analysis, mass spectroscopy, and X‐ray diffraction analysis (compounds 4 – 12 , 14 , and 15 ) techniques. In vitro antifungal activity tests were performed for all of the synthesized compounds. Inhibition zones, percentage of inhibition, minimum fungicidal activity, minimum inhibitory concentration, and lethal dose values of the target compounds were determined against some plant pathogens. According to the results of the biological activity tests, all of the synthesized compounds showed moderate to high levels of antifungal activity. Theoretical calculations were performed to support the experimental results. The geometric parameters of selected compounds ( 5 , 6 , and 8 ) were optimized using the density functional theory B3LYP/6‐31G(d) method in the Gaussian 09W package program, and the frontier molecular orbitals (highest occupied molecular orbital–lowest unoccupied molecular orbital) were calculated theoretically. Finally, molecular docking studies were performed for antifungal activity studies of the selected compounds and to determine whether or not these compounds could be inhibitor agents for the 2RKV protein structure.     

Thiourea Derivatives,Simple in Structure but Efficient Enzyme Inhibitors and Mercury Sensors

In this study six unsymmetrical thiourea derivatives, 1-isobutyl-3-cyclohexylthiourea (1), 1-tert-butyl-3-cyclohexylthiourea (2), 1-(3-chlorophenyl)-3-cyclohexylthiourea (3), 1-(1,1-dibutyl)-3-phenylthiourea (4), 1-(2-chlorophenyl)-3-phenylthiourea (5) and 1-(4-chlorophenyl)-3-phenylthiourea (6) were obtained in the laboratory under aerobic conditions. Compounds 3 and 4 are crystalline and their structure was determined for their single crystal. Compounds 3 is monoclinic system with space group P2₁/n while compound 4 is trigonal, space group R³:H. Compounds (1–6) were tested for their anti-cholinesterase activity against acetylcholinesterase and butyrylcholinesterase (hereafter abbreviated as, AChE and BChE, respectively). Potentials (all compounds) as sensing probes for determination of deadly toxic metal (mercury) using spectrofluorimetric technique were also investigated. Compound 3 exhibited better enzyme inhibition IC₅₀ values of 50, and 60 µg/mL against AChE and BChE with docking score of −10.01, and −8.04 kJ/mol, respectively. The compound also showed moderate sensitivity during fluorescence studies.     

Synthesis,enzymes inhibitory properties and characterization of 2- (bis (4-aminophenyl) methyl) butan-1-ol compound: Quantum simulations,and in-silico molecular docking studies

In this study to be presented, the BAPMB molecule was synthesized and structurally characterized. All calculations were applied using the detailed DFT/B3LYP method with 6-311G (d, p) and SDD depended on the stable phase geometry of the molecule. Also, various HOMO-LUMO energy gaps, inter-orbital intramolecular interactions of the natural bond, and electro-static surface mapping actions were also realized. The molecule was characterized by NMR spectroscopic analysis. Besides, LC/MS data were acquired. In this analysis, fragment ions (m/z 168.9) of BAPMB were obtained as 137.8, 179.9, 198, 201.5, and 228.0 approximately. Also, molecular docking was performed while examining the exact binding site and binding mechanism of the ligand on the protein. In the study, glide scores in binding affinity with BAPMB – AChE, BAPMB – BChE, and BAPMB – GST, respectively; It was found to be −7.228 ​cal/mol, −7.205 ​cal/mol, −6.07 ​cal/mol and BAPMB - AChE was found to be more effective with receptor binding score. BAPMB was analyzed for its inhibition features counter AChE, BChE, and GST enzymes that exhibit effective inhibition. AChE, BChE, GST enzymes were powerfully inhibited by BAPMB. BChE showed excellent activity, particularly in comparison to standard tacrine. Eventually, AIM analysis was performed to search intermolecular interactions in the BAPMB compound.     

Synthesis and biological activity of 3,6-diaryl-7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives as novel acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors played significant roles in treatment of Alzheimer’s disease. Based on the research foundation of our previous work and molecular modeling, twelve 3,6-diaryl-7H-thiazolo[3,2-b][1,2,4]triazin-7-one derivatives were synthesized and characterized by mass spectra, infrared spectra, NMR and elemental analyses. The study of AChE inhibitory activity was carried out using the Ellman colorimetric assay with huperzine-A as the positive control. All target compounds exhibited more than 40% inhibition at 10 μM. Some target compounds showed good inhibition against AChE. The preliminary structure-activity relationships were the halogen atoms at the phenyl ring at the C6 position, the hydroxy groups and the long side chains at the phenyl ring at the C3 position of the parent nucleus played significant roles in the AChE inhibitory activity of the target compounds.