Reactivation by novel pyridinium oximes of rat serum and skeletal muscle acetylcholinesterase inhibited by organophosphates.

The treatment of organophosphate (OP) anticholinesterases currently lacks an effective oxime reactivator of OP-inhibited acetylcholinesterase (AChE) which can penetrate the blood-brain barrier (BBB). Our laboratories have synthesized novel substituted phenoxyalkyl pyridinium oximes and tested them for their ability to promote survival of rats challenged with lethal doses of nerve agent surrogates. These previous studies demonstrated the ability of some of these oximes to promote 24-h survival to rats challenged with a lethal level of highly relevant surrogates for sarin and VX. The reactivation of OP-inhibited AChE in peripheral tissues was likely to be a major contributor to their efficacy in survival of lethal OP challenges. In the present study, twenty of these novel oximes were screened in vitro for reactivation ability for AChE in rat skeletal muscle and serum using two nerve agent surrogates: phthalimidyl isopropyl methylphosphonate (PIMP, a sarin surrogate) and 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate). The oximes demonstrated a range of 23%-102% reactivation of AChE in vitro across both tissue types. Some of the novel oximes tested in the present study demonstrated the ability to more effectively reactivate AChE in serum than the currently approved oxime, 2-PAM. Therefore, some of these novel oximes have the potential to reverse AChE inhibition in peripheral target tissues and contribute to survival efficacy.

Deciphering the multi-functional role of Indian propolis for the management of Alzheimer's disease by integrating LC-MS/MS, network pharmacology, molecular docking, and in-vitro studies.

The conventional one-drug-one-disease theory has lost its sheen in multigenic diseases such as Alzheimer's disease (AD). Propolis, a honeybee-derived product has ethnopharmacological evidence of antioxidant, anti-inflammatory, antimicrobial and neuroprotective properties. However, the chemical composition is complex and highly variable geographically. So, to leverage the potential of propolis as an effective treatment modality, it is essential to understand the role of each phytochemical in the AD pathophysiology. Therefore, the present study was aimed at investigating the anti-Alzheimer effect of bioactive in Indian propolis (IP) by combining LC-MS/MS fingerprinting, with network-based analysis and experimental validation. First, phytoconstituents in IP extract were identified using an in-house LC-MS/MS method. The drug likeness and toxicity were assessed, followed by identification of AD targets. The constituent-target-gene network was then constructed along with protein-protein interactions, gene pathway, ontology, and enrichment analysis. LC-MS/MS analysis identified 16 known metabolites with druggable properties except for luteolin-5-methyl ether. The network pharmacology-based analysis revealed that the hit propolis constituents were majorly flavonoids, whereas the main AD-associated targets were MAOB, ESR1, BACE1, AChE, CDK5, GSK3ß, and PTGS2. A total of 18 gene pathways were identified to be associated, with the pathways related to AD among the topmost enriched. Molecular docking analysis against top AD targets resulted in suitable binding interactions at the active site of target proteins. Further, the protective role of IP in AD was confirmed with cell-line studies on PC-12, in situ AChE inhibition, and antioxidant assays.

Synthesis and investigation of new indole-containing vinyl sulfide derivatives: In silico and in†vitro studies for potential therapeutic applications.

Indoles featuring organosulfur compounds serve as privileged structural scaffolds in various biologically active compounds. This study investigates the biological properties of five synthetic sulphenyl vinyl indoles (3 a-e) using both in silico and in vitro methods. Computational analyses employing Swiss ADME and Molinspiration software reveal the remarkable inhibitory activity of compound 3 d against proteases and kinases (scores of 0.18 and 0.06, respectively). Furthermore, it demonstrates the ability to modulate ionic and G protein-coupled receptors (scores: -0.06 and 0.31, respectively) and serves as a ligand for nuclear receptors (score 0.15). In vitro investigations highlight the compounds' efficacy in countering ABTS+ radical attacks and reducing lipid peroxidation levels. Particularly noteworthy is the superior efficacy of compounds 3 a, 3 b, and 3 e in DPPH (EC50 3 a: 268.5 µM) and TEAC assays (EC50 3 a: 49.9 µM; EC50 3 b: 133.4 µM, and EC50 3 e: 84.9 µM), as well as TBARS levels. Compound 3 c significantly reduces acetylcholinesterase activity, positioning itself as a noteworthy enzyme inhibitor. This study emphasizes the versatile biological potential of synthetic indole derivatives, suggesting their applicability for therapeutic purposes.

Exploring Astrodaucus orientalis (L.) Drude: Phytochemical Analysis and its Biological Potential Against Alzheimer's and Diabetes.

In current study antioxidant, antidiabetic, antimicrobial, anticholinesterase, and human carbonic anhydrase I, and II (hCA I and II) isoenzymes inhibition activities of Astrodaucus orientalis different parts were investigated. Achetylcholinesterse (AChE) and butyrylcholinesterse (BChE) inhibitory activities of octyl acetate were determined via molecular docking. Quantitative assessment of specific secondary metabolites was conducted using LC-MS/MS. An examination of chemical composition of essential oils was carried out by GC-MS/MS. A thorough exploration of plant's anatomical characteristics was undertaken. The highest phenolics level and DPPH antioxidant capacity were seen in root and fruit. Fruit essential oil demonstrated the highest AChE inhibition (44.13±3.61 %), while root dichloromethane sub-extract had the best inhibition towards BChE (86.13±2.58 %). Cytosolic hCA I, and II isoenzymes were influentially inhibited by root oil with 1.974 and 2.207 µM IC50 values, respectively. The most effective extracts were found to be root all extract/sub-extracts (except water) against C. tropicalis and C. krusei strains with MIC value 160>µg/mL. Sabinene (29.4 %), α-pinene (20.2 %); octyl acetate (54.3 %); myrcene (28.0 %); octyl octanoate (71.3 %) were found principal components of aerial parts, roots, flowers, and fruits, respectively. Flower essential oil, fruit dicloromethane and ethyl acetate exhibited potent α-glucosidase inhibitory activity with 900, 40, and 937 µg/mL IC50 values, respectively.

Chemical Characterization, Phenolic Compounds Quantification, and Assessment of Antioxidant and Anti-Acetylcholinesterase Activities of Byrsonima sericea DC fruits.

Byrsonima sericea is a species native to Brazil that is widely used in traditional medicine. The seed ethanol extract (SEE) had the highest content of total phenols (179.35 mg GAE g-1 extract) and flavonoids (10.42 mg QE g-1 extract) and was the most active in relation to antioxidant activity (DPPH: IC50 =4.25 µg mL-1 and ABTS: IC50 =4.82 µg mL-1 ). The peel/pulp ethanol extract (PEE) had the best anticholinesterase activity (IC50 =6.02 µg mL-1 ). Chromatographic investigation identified gallic acid, isoquercitrin, quercetin and amentoflavone in SEE, and gallic acid, isoquercitrin, quercetin and rutin in PEE. Six fatty acid methyl esters and seven triterpenes were identified, highlighting oleic acid in the seed hexane extract (61.85 %) and in the peel/pulp hexane extract (52.61 %), and betulin in the peel/pulp hexane extract (5.25 %). The substances and biological activities identified in B. sericea characterize this fruit as a functional food for future studies.

Variability of Isoquinoline Alkaloid Profiles and Anticholinesterase Activities with Binding-Mode Predictions of Glaucium flavum Population.

In this study, phytochemical and biological activity studies supported by docking were carried out on a species of the genus Glaucium, a repository of isoquinoline alkaloids. The GC-MS (Gas Chromatography-Mass Spectrometry) method is used to characterize the isoquinoline alkaloids of Glaucium flavum Crantz. (Papaveraceae). G. flavum was collected from seven different regions of Türkiye (Antalya, Urla-Izmir, Mordogan-Izmir, Mugla, Assos-Canakkale, Karabiga-Canakkale, Giresun) and totally 17 compounds were detected by GC-MS. Glaucine was found to be the major constituent in the sample collected from Mugla, whereas isocorydine was recorded to be the principal alkaloid in other samples. Further fractionation studies on G. flavum collected from Antalya province in Southwestern Türkiye, yielded five major alkaloids (isocorydine 1, dihydrosanguinarine 2, glaucine 3, dehydroglaucine 4, protopine 5) which were characterized by spectroscopic methods. Anticholinesterase activities of the extracts and isolated alkaloids were also tested by in vitro Ellman method. The isolated compounds were also analyzed by a molecular docking technique to determine the binding orientations in the gorge of the active site of acetylcholinesterase (AChE) and a homology model of butyrylcholinesterase (BuChE). This is the first comparative investigation of the phytochemical composition and biodiversity of Glaucium flavum species growing in Türkiye.

LC-MS and GC-MS Analyses on Green Algae Penicillus Capitatus: Cytotoxic, Antimicrobial and Anticholinesterase Activity Screening Enhanced by Molecular Docking & Dynamics and ADME Studies.

In this comprehensive screening study, the chemical composition, and cytotoxic, antimicrobial, and anticholinergic activities of the green algae Penicillus capitatus, collected from Antalya-Türkiye, were determined as in vitro and in silico. GC-MS analysis of the hexane extract revealed a high content of fatty acids, with hexadecanoic acid constituting half of the total fatty acid content. LC-HRMS analysis of the DCM:MeOH extract identified ascorbic acid as the most abundant compound, followed by (-)-epigallocatechin and salicylic acid. The DCM:MeOH extract exhibited potent cytotoxicity against MDA-MB-231 and MCF7 breast cancer cell lines, outperforming doxorubicin with lower IC50 values and a higher selectivity index. Additionally, the extract demonstrated significant antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Candida albicans, along with selective inhibition of acetylcholinesterase (hAChE) over butyrylcholinesterase (hBChE). Molecular docking and dynamics studies revealed that apigenin-7-O-glucoside and epigallocatechin form stable interactions with estrogen receptor alpha (ERα) and hAChE, suggesting their potential as inhibitors. In silico ADME studies indicated favorable pharmacokinetic profiles for the detected compounds, supporting their potential as drug candidates. The promising cytotoxic activity of the P. capitatus extracts, coupled with significant antimicrobial properties and selective hAChE inhibition, highlights their therapeutic potential for breast cancer treatment, infection management, and neurodegenerative disease intervention.

Synthesis and molecular docking simulation of new benzimidazole-thiazole hybrids as cholinesterase inhibitors.

Dementia is a cognitive disturbance that is generally correlated with central nervous system diseases, especially Alzheimer's disease. The limited number of medications available is insufficient to improve the lifestyle of the patients suffering from this disease. Thus, new benzimidazole-thiazole hybrids (3-10) were designed and synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory agents. The in vitro evaluation displayed that the derivatives 4b, 4d, 5b, 6a, 7a, and 8b demonstrated dual inhibitory efficiency against both AChE with IC50 ranging from 4.55 to 8.62 µM and BChE with IC50 ranging from 3.50 to 8.32 µM. By analyzing the Lineweaver-Burk plot, an uncompetitive form of inhibition was determined for the highly active compound 4d, revealing its inhibition type. The human telomerase reverse transcriptase-immortalized retinal pigment epithelial cell line was used to ensure the safety of the most potent cholinesterase inhibitors. Furthermore, compounds 4b, 4d, 5b, 6a, 7a, and 8b were evaluated for their neuroprotective and antioxidant properties, as well as their ability to suppress COX-2. The results demonstrated that compounds 4d, 5b, and 8b presented significant neuroprotection efficiency against H2 O2 -induced damage in SH-SY5Y cells with % cell viability of 67.42 ± 7.90%, 62.51 ± 6.71%, and 72.61 ± 8.10%, respectively, while the tested candidates did not reveal significant antioxidant activity. Otherwise, compounds 4b, 6a, 7a, and 8b displayed outstanding COX-2 inhibition effects with IC50 ranging from 0.050 to 0.080 µM relative to celecoxib (IC50 = 0.050 µM). In addition, molecular docking was carried out for the potent benzimidazole-thiazole hybrids with the active sites of both AChE (PDB ID: 4EY7) and BChE (PDB code: 1P0P). The tested candidates fit well in the active sites of both portions, with docking scores ranging from -8.65 to -6.64 kcal/mol (for AChE) and -8.71 to -7.73 kcal/mol (for BChE). In silico results show that the synthesized benzimidazole-thiazole hybrids have good physicochemical and pharmacokinetic properties with no Lipinski rule violations. The preceding results exhibited that compound 4d could be used as a new template for developing more significant cholinesterase inhibitors in the future.

Design, synthesis, in silico, and in vitro evaluation of novel benzyloxybenzene substituted (S)-α-amino amide derivatives as cholinesterases and monoaminoxidases inhibitor.

In this study, a series of novel benzyloxybenzene substituted (S)-α-amino acid methyl esters and their amide derivatives were synthesized and evaluated for their inhibitory actions against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B). The synthetic strategy was based on starting from benzyl bromide (5) and 4-hydroxybenzaldehyde (6). The reaction of 5 and 6 in the presence of K2 CO3 gave benzyloxybenzaldehyde 7. Benzyloxybenzene substituted (S)-α-amino acid methyl esters 11, 12, 13, (±)-19, and (±)-20 were obtained from the reaction of  L-amino acid methyl esters with benzyloxybenzaldehyde (7) followed by in situ reduction with NaBH4 . The reaction of (S)-11, (S)-12, 13, (±)-19, and (±)-20 with excess ammonia gave amides (S)-14, (S)-15, 16, (±)-21, and (±)-22. The in vitro inhibitory activities of compounds against MAO-A, MAO-B, AChE, and BChE were investigated. Within the α-amino acid methyl ester series, 13 (21.32 ± 0.338 µM) showed selectivity by inhibiting the MAO-B better than MAO-A. 13 emerged as the most active member of this series, exhibiting a 12-fold selectivity for MAO-B. 14 (4.501 ± 0.295 µM) demonstrated a pronounced selectivity for MAO-A over MAO-B, with a selectivity ratio of 110-fold. In addition, it was determined that compound 15 (95.65 ± 3.09 µM) had high selectivity for BChE inhibition. 21 was demonstrated the most potent inhibition (18.36 ± 1.36 µM) against AChE.

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer's Disease: An In Vitro and In Vivo Investigation.

A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer's disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic ß-amyloid (Aß42) species in human neuronal cells in response to treatment. Among the most promising compounds were 3a and 3c, which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD50 (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.

Polyphenols Investigation and Antioxidant and Anticholinesterase Activities of Rosmarinus officinalis L. Species from Southwest Romania Flora.

Rosemary is one of the most important medicinal plants for natural therapy due to its multiple pharmacological properties, such as antioxidant, anti-inflammatory, neuroprotective, antiproliferative, antitumor, hepato- and nephroprotective, hypolipidemic, hypocholesterolemic, antihypertensive, anti-ischemic, hypoglycemic, radioprotective, antimicrobial, antiviral, antiallergic, and wound healing properties. Our study reports for the first time, over a 12-month period, the identification and quantification of polyphenols and the investigation of the antioxidant and acetylcholinesterase (AChE) inhibitory activities of the Rosmarinus officinalis L. species harvested at flowering from the flora of southwestern Romania (Oltenia Region). Identification and quantification of polyphenolic acids was made by ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS). Total phenolic content was determined using the spectrophotometric method. In situ antioxidant and anticholinesterase activities were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and AChE inhibitory assay, respectively, on high-performance thin-layer chromatography (HPTLC) plates. DPPH radical scavenging activity was also assessed spectrophotometrically. The results revealed significant correlations between specific polyphenolic compounds and the measured biological activities, understanding the role of seasonal variations and providing insights into the optimal harvesting times and medicinal benefits of rosemary. Our research brings new information on the phytochemical profile of R. officinalis as a natural source of polyphenols with antioxidant and AChE inhibitory properties.

African Under-Utilized Medicinal Leafy Vegetables Studied by Microtiter Plate Assays and High-Performance Thin-Layer Chromatography-Planar Assays.

Biological activities of six under-utilized medicinal leafy vegetable plants indigenous to Africa, i.e., Basella alba, Crassocephalum rubens, Gnetum africanum, Launaea taraxacifolia, Solanecio biafrae, and Solanum macrocarpon, were investigated via two independent techniques. The total phenolic content (TPC) was determined, and six microtiter plate assays were applied after extraction and fractionation. Three were antioxidant in vitro assays, i.e., ferric reducing antioxidant power (FRAP), cupric reduction antioxidant capacity (CUPRAC), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging, and the others were enzyme (acetylcholinesterase, butyrylcholinesterase, and tyrosinase) inhibition assays. The highest TPC and antioxidant activity from all the methods were obtained from polar and medium polar fractions of C. rubens, S. biafrae, and S. macrocarpon. The highest acetyl- and butyrylcholinesterase inhibition was exhibited by polar fractions of S. biafrae, C. rubens, and L. taraxacifolia, the latter comparable to galantamine. The highest tyrosinase inhibition was observed in the n-butanol fraction of C. rubens and ethyl acetate fraction of S. biafrae. In vitro assay results of the different extracts and fractions were mostly in agreement with the bioactivity profiling via high-performance thin-layer chromatography-multi-imaging-effect-directed analysis, exploiting nine different planar assays. Several separated compounds of the plant extracts showed antioxidant, α-glucosidase, α-amylase, acetyl- and butyrylcholinesterase-inhibiting, Gram-positive/-negative antimicrobial, cytotoxic, and genotoxic activities. A prominent apolar bioactive compound zone was tentatively assigned to fatty acids, in particular linolenic acid, via electrospray ionization high-resolution mass spectrometry. The detected antioxidant, antimicrobial, antidiabetic, anticholinesterase, cytotoxic, and genotoxic potentials of these vegetable plants, in particular C. rubens, S. biafrae, and S. macrocarpon, may validate some of their ethnomedicinal uses.

Chalcones bearing nitrogen-containing heterocyclics as multi-targeted inhibitors: Design, synthesis, biological evaluation and molecular docking studies.

In this work, a series of chalcones (1a-d, 2a-d, 3a-d, 4a-d, and 5a-d) were designed and synthesized by Claisen-Schmidt condensation. Also, their chemical structures were elucidated using UV-Vis, FT IR, 1 H NMR, 13 C NMR, MS spectral data, and elemental analyses. Subsequently, the anticholinesterase, tyrosinase, urease inhibitory activities and antioxidant activities of all chalcones were evaluated. The inhibitory potential of all chalcones in terms of IC50 value was observed to range from 7.18 ± 0.43 to 29.62 ± 0.30 µM against BChE by comparing with Galantamine (IC50 46.06 ± 0.10 µM) as a reference drug. Also, compounds 2c, 3c, 4c, 4b, and 4d exhibited high anticholinesterase activity against both AChE and BChE enzymes. The tyrosinase inhibitory activity results revealed that three compounds (IC50 1.75 ± 0.83 µM for 2b, IC50 2.24 ± 0.11 µM for 3b, and IC50 1.90 ± 0.64 µM for 4b) displayed good inhibitory activity against tyrosinase compared with kojic acid (IC50 0.64 ± 0.12 µM). In addition, other different three chalcones (IC50 22.34 ± 0.25 µM for 2c, IC50 20.98 ± 0.08 µM for 3c, and IC50 18.26 ± 0.13 µM for 4c) showed excellent inhibitory activity against the urease by comparing with thiourea (IC50 23.08 ± 0.19 µM). Compounds 3c and 4c showed the best potency in all antioxidant activity tests. In light of these findings, the structure-activity relationship for compounds was also described. Furthermore, molecular modeling studies, including molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and pharmacophore analyses of compounds, gave important information about the interactions and drug-likeness properties. As a result, all chalcones exhibited suitable ADMET findings, predicting good oral bioavailability.

Investigation of biological activities of various 1,2,3-triazole compounds: Their effects on cholinesterase enzymes, determination of antioxidant capacity and antimicrobial activity.

1,2,3-triazoles are pharmaceutically significant compounds that have attracted recent interest from medicinal chemists because of their important biological activities. Addressed herein, some 1,2,3-triazoles were synthesized to investigate the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes, antioxidant capacity, and antimicrobial effect. The antioxidant profile of 1,2,3-triazoles determined by varied bioanalytical antioxidant methods, including 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS.+ ), 1,1-diphenyl-2-picrylhydrazil (DPPH·), cupric ion (Cu2+ ) and ferric ion (Fe3+ ) ascorbic acid, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) were used as the standard compounds. In addition, the antibacterial and antifungal activities of these compounds were investigated against seven bacteria and three fungal species using the hollow agar method. As a result of these studies, it was determined that compound 4 showed the best antimicrobial activity and antioxidant activity close to the standards. Inhibitory effects and kinetic studies of these molecules on cholinesterase enzymes were performed. According to the results obtained, compound 4 showed stronger AChE inhibition and compound 3 stronger BChE inhibition compared to other compounds. In kinetic studies, it was found that AChE showed noncompetitive inhibition by compound 4, and BChE showed competitive inhibition by compound 3.

Anatomical, Morphological, and Chemical Characterizations and Biological Activities of Gagea taurica Steven (Liliaceae): A New Record for the Turkish Flora.

Gagea genus, which is native to the Mediterranean and Black Sea regions, has attracted significant attention due to its biodiversity and potential health benefits. In this study, the biochemical composition and biological activities of methanol extracts from various parts of G. taurica were investigated, along with their anatomical and morphological characteristics. The best antimicrobial activity was found to be MeOH extracts of corm and leaf against several Candida strains with MIC=640 µg/mL. The highest level of phenolics together with significant results of antioxidant activities were observed in flowers extracts. The α-amylase inhibition assay results showed that the highest inhibition percentage was observed with acarbose (59 %), followed by leaf extract (43 %). Leaf exhibited the most effective inhibitory activity in AChE inhibition assay, whereas flower demonstrated the most significant inhibitory activity in BChE inhibition assay. Hesperidin was found as 1621.0001 ng/ml value in flower extract and 283.9339 ng/ml value leaf.

Comparative Analysis of Antioxidant, Anticholinesterase, and Antibacterial Activity of Microbial Chondroitin Sulfate and Commercial Chondroitin Sulfate.

Chondroitin synthesis was performed using the recombinant Escherichia coli(C2987) strain created by transforming the plasmid pETM6-PACF-vgb, which carries the genes responsible for chondroitin synthesis, kfoA, kfoC, kfoF, and the Vitreoscilla hemoglobin gene (vgb). Then, Microbial chondroitin sulfate (MCS)'s antioxidant, anticholinesterase, and antibacterial activity were compared with commercial chondroitin sulfate (CCS). The antioxidant studies revealed that the MCS and CCS samples could be potential targets for scavenging radicals and cupric ion reduction. MCS demonstrated better antioxidant properties in the ABTS assay with the IC50 value of 0.66 mg than CCS. MCS showed 2.5-fold for DPPH and almost 5-fold for ABTS⋅+ (with a value of 3.85 mg/mL) better activity than the CCS. However, the compounds were not active for cholinesterase enzyme inhibitions. In the antibacterial assay, the Minimum inhibitory concentration (MIC) values of MCS against S. aureus, E. aerogenes, E. coli, P. aeruginosa, and K. pneumoniae (0.12, 0.18, 0.12, 0.18, and 0.18 g/mL, respectively) were found to be greater than that of CCS (0.42, 0.48, 0.36, 0.36, and 0.36 g/mL, respectively). This study demonstrates that MCS is a potent pharmacological agent due to its physicochemical properties, and its usability as a therapeutic-preventive agent will shed light on future studies.

Metabolomic Analysis and in Vitro Investigation of the Biological Properties of a By-Product Derived from Vicia faba.

By-products from plant sources are recently regarded as a valuable source of bioactive compounds. In this regard, the present study aims to assess the bioactivities of the 70 % MeOH extract obtained from Vicia faba peels and analyze its metabolomic profile. Acetylcholinesterase and carbohydrate metabolizing enzymes inhibitory activities of the plant extract were assayed using quantitative colorimetric tests. Antioxidant activity was estimated by DPPH assay, and cytotoxic activity was evaluated against normal fibroblast skin cells (1-BJ1). Ninety-one metabolites were tentatively identified using ultra-high-performance liquid chromatography (UHPLC) hyphenated with quadrupole-time-of-flight tandem mass spectrometry (QTOF-MS). Most of these compounds were described for the first time in the plant. In addition, catechin, rutin, quercitrin, and rhamnetin were isolated from the plant extract. The plant extract and the isolated compounds possessed no cytotoxic activity on (1-BJ1), while they exhibited anticholinesterase with the highest activity for 70 % MeOH extract (IC50 =120.11 mg/L), antioxidant potential with the highest activity for rutin (90.54±0.73 %), and carbohydrate metabolizing inhibitory activities with the highest activity for rutin. These discoveries imply that V. faba peels might serve as an efficient antioxidant, exhibit anticholinesterase properties, and have the potential for use in managing diabetes, all while avoiding cytotoxicity in normal cells.

Discovery selective acetylcholinesterase inhibitors to control Tetranychus urticae (Acari: Tetranychidae).

The two-spotted spider mite, Tetranychus urticae Koch, has a broad host plant range and presents an extreme capacity for developing pesticide resistance, becoming a major economic pest in agriculture. Anticholinesterase insecticides still account for a big part of global insecticide sales. However, there is a growing concern about the serious resistance problems of anticholinesterase insecticides and their nontarget toxicity. In this study, structure-based virtual screening was performed to discover selective AChE inhibitors from the ChemBridge database, and 39 potential species-specific AChE inhibitor were obtained targeting T. urticae AChE, but not human AChE. Among them, compound No. 8 inhibited AChE from T. urticae, but not from human, and had an inhibitory activity comparable to that of eserine. Compound No. 8 had dose-dependent toxicity to T. urticae in glass slide-dipping assay and had significant mite control effects in a pot experiment, but required a high concentration to achieve similar control effects to spirodiclofen. The toxicity evaluation suggested that compound No. 8 had no acute toxicity on pollinator honey bees and natural predator N. californicus and did not affect strawberry growth in our assay. Compound No. 8 is a potential lead compound for developing novel acaricides with reduced nontarget toxicity.

Design, synthesis, and biological evaluation of thienopyrimidine derivatives as multifunctional agents against Alzheimer's disease.

A series of 12 S-substituted tetrahydrobenzothienopyrimidines were designed and synthesized based on the donepezil scaffold. All the newly synthesized compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and the most active compounds were tested for their butyrylcholinesterase (BuChE) inhibitory activity. Moreover, all the synthesized compounds were evaluated for their inhibitory effects against Aß aggregation and antioxidant activity using the oxygen radical absorbance capacity method. Compounds 4b, 6b, and 8b displayed the most prominent AChE inhibitory action comparable to donepezil. Compound 6b showed the greatest AChE inhibitory action (IC50 = 0.07 ± 0.003 µM) and the most potent BuChE inhibitory action (IC50 = 0.059 ± 0.004 µM). Furthermore, the three compounds exhibited significant antioxidant activity. Compounds 6b and 8b exerted more inhibitory action on Aß aggregation than donepezil. The cytotoxic activity of compounds 4b, 6b, and 8b against the WI-38 cell line in comparison with donepezil was examined using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. The results revealed that compounds 6b and 8b were less cytotixic than donepezil, while compound 4b showed nonsignificant cytotoxicity compared to donepezil. For more insights about the binding patterns of the most promising compounds (4b, 6b, and 8b) with the AChE at molecular levels; molecular docking and molecular dynamics simulations were performed. The density functional theory calculations and absorption, distribution, metabolism, excretion and toxicity properties were described as well. The results highlighted compound 6b, which incorporates a phenylpiperazine moiety coupled to a thienopyrimidone scaffold via two-atom spacer, to be a promising multifunctional therapeutic agent for the treatment of Alzheimer's disease. It is a potent dual AChE and BuChE inhibitor. Furthermore, it had stronger Aß aggregation inhibitory action than donepezil. Additionally, compound 6b exerted significant antioxidant activity.

Evaluation of Antimicrobial, Anticholinesterase Potential of Indole Derivatives and Unexpectedly Synthesized Novel Benzodiazine: Characterization, DFT and Hirshfeld Charge Analysis.

The pharmacological effectiveness of indoles, benzoxazepines and benzodiazepines initiated our synthesis of indole fused benoxazepine/benzodiazepine heterocycles, along with enhanced biological usefulness of the fused rings. Activated indoles 5, 6 and 7 were synthesized using modified Bischler indole synthesis rearrangement. Indole 5 was substituted with the trichloroacetyl group at the C7 position, yielding 8, exclusively due to the increased nucleophilic character of C7. When trichloroacylated indole 8 was treated with basified ethanol or excess amminia, indole acid 9 and amide 10 were yielded, respectively. Indole amide 10 was expected to give indole fused benoxazepine/benzodiazepine 11a/11b on treatment with alpha halo ester followed by a coupling agent, but when the reaction was tried, an unexpectedly rearranged novel product, 1,3-bezodiazine 12, was obtained. The synthetic compounds were screened for anticholinesterase and antibacterial potential; results showed all products to be very important candidates for both activities, and their potential can be explored further. In addition, 1,3-bezodiazine 12 was explored by DFT studies, Hirshfeld surface charge analysis and structural insight to obrain a good picture of the structure and reactivity of the products for the design of derivatised drugs from the novel compound.