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Enzymes are molecules that play a crucial role in maintaining homeostasis and balance in all living organisms by catalyzing metabolic and cellular processes. If an enzyme's mechanism of action is inhibited, the progression of certain diseases can be slowed or halted, making enzymes a key therapeutic target. Therefore, identifying or developing enzyme inhibitors is essential for treating significant diseases and ensuring plant defense against pathogens. This review aims to compile information on various types of enzyme inhibitors, particularly those that are well studied and beneficial in both human and plant contexts, by analyzing their mechanisms of action and the resulting benefits. Specifically, this review focuses on three different types of enzyme inhibitors that are most studied, recognized, and cited, each with distinct areas of action and potential benefits. For instance, serine enzyme inhibitors in plants help defend against pathogens, while the other two classes—alpha-glucosidase inhibitors and carbonic anhydrase inhibitors—have significant effects on human health. Furthermore, this review is also intended to assist other researchers by providing valuable insights into the biological effects of specific natural or synthetic inhibitors. Based on the current understanding of these enzyme inhibitors, which are among the most extensively studied in the scientific community, future research could explore their use in additional applications or the development of synthetic inhibitors derived from natural ones. Such inhibitors could aid in defending against pathogenic organisms, preventing the onset of diseases in humans, or even slowing the growth of certain pathogenic microorganisms. Notably, carbonic anhydrase inhibitors have shown promising results in potentially replacing antibiotics, thereby addressing the growing issue of antibiotic resistance. [ABSTRACT FROM AUTHOR]

Synthesis and properties of tetrahydroxy substituted zinc phthalocyanine is reported. UV–Visible spectrum for the aggregation properties of the compound and fluorescence properties were examined by excitation, emission spectra. This complex was an inhibitor of butyrylcholinesterase (BChE), α-Gly, α-Amy, and acetylcholinesterase (AChE) enzymes for tetra- hydroxy phthalocyaninato zinc (II) 3 with IC50 values of 49.18 μM for α-Amy, 110.85 μM for BChE, 35.13 μM for α-glycosidase and 54.63 μM for AChE, respectively. On the otherside, within the scope of computational study, in vitro activity behavior and states of the related complex, which cannot be explained experimentally, were evaluated at atomic level. The pharmacodynamics properties of the complex (3) were elucidated by molecular docking against four target enzymes, AChE, BChE, α-Gly and α-Amy. After that, its potential drug candidate was investigated based on its pharmacokinetic properties with help of in silico-ADMET analysis. As a result of all the applications, a desired goal in medicinal chemistry was to develop new, reliable and safe cholinesterase and α-glycosidase inhibitors with high efficacy. [ABSTRACT FROM AUTHOR]

A talented endophytic Streptomyces sp. PH9030 is derived from the medicinal plant Kadsura coccinea (Lem.) A.C. Smith. The undescribed naphthoquinone naphthgeranine G (5) and seven previously identified compounds, 6–12, were obtained from Streptomyces sp. PH9030. The structure of 5 was identified by comprehensive examination of its HRESIMS, 1D NMR, 2D NMR and ECD data. The inhibitory activities of all the compounds toward α-glucosidase and their antibacterial properties were investigated. The α-glucosidase inhibitory activities of 5, 6, 7 and 9 were reported for the first time, with IC50 values ranging from 66.4 ± 6.7 to 185.9 ± 0.2 μM, as compared with acarbose (IC50 = 671.5 ± 0.2 μM). The molecular docking and molecular dynamics analysis of 5 with α-glucosidase further indicated that it may have a good binding ability with α-glucosidase. Both 9 and 12 exhibited moderate antibacterial activity against methicillin-resistant Staphylococcus aureus, with minimum inhibitory concentration (MIC) values of 16 μg/mL. These results indicate that 5, together with the naphthoquinone scaffold, has the potential to be further developed as a possible inhibitor of α-glucosidase. [ABSTRACT FROM AUTHOR]

Current antidiabetic medications have a plethora of harmful side effects, and most of the drugs do not contain 1,3,4-oxadiazole moiety. Therefore, research into the development of novel drugs which contain 1,3,4-oxadiazole moiety with fewer side effects is necessary. Novel fluorine-incorporated 1,3,4-oxadiazole derivatives (1c–1n) were synthesized, characterized, and evaluated for α-amylase and α-glucosidase enzyme inhibitor activity. An in vivo Drosophila melanogaster model and an in vitro system were used to investigate its antidiabetic properties, further, which were characterized by 1HNMR, MASS, and FT-IR. Spectroscopic techniques and DFT are used to calculate more geometrically optimized molecule structures using the B3LYP technique. The compounds were tested against the α-glucosidase and α-amylase enzymes. Among different compounds tested, compounds 1i (IC50 = 54.83 µg/ml), 1k (IC50 = 64.95 µg/ml), 1m (IC50 = 64.78 µg/ml), and 1n (IC50 = 66.30 µg/ml) showed significant α-amylase inhibitor efficacy compared to the acarbose (IC50 = 35.17 µg/ml); compounds 1m (IC50 = 74.64 µg/ml) and 1i (IC50 = 60.35 µg/ml) exhibited significant α-glucosidase inhibitory action compared to acarbose (IC50 = 46.06 µg/ml). The docking study exhibited that compound 1i creates six hydrogen bonds and compound 1m forms three hydrogen bonding contacts at the active site of the enzyme (PDBID:4w93). The obtained results are demonstrated that compounds 1i, 1m, 1n, and 1k had greater antidiabetic activities and can be further taken into consideration for antidiabetic therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objectives: The aim is to discover α-glucosidase/acetylcholinesterase inhibitors as lead compounds from a traditional herbal prescription of Qi-Li-Qiang-Xin capsule (QLQX). Methods: A novel strategy combining time-based fractionation, LC-QTOF-MS, enzymatic activity assay, molecular docking and component-target association analysis was performed to discover α-glucosidase/acetylcholinesterase inhibitors from QLQX. Time-based fractionation combined with enzymatic activity assay was used to find the distribution period of active compounds in the herbal prescription. LC-QTOF-MS was used to analyze the structure of active compounds. Molecular docking was applied to explore the interaction between active compounds and targets. Results: According to time-based fractionation, the active components of QLQX for acetylcholinesterase were primarily concentrated in the highly polar region, whereas the active components for α-glucosidase were predominantly found in the moderately polar area. A total of 33 compounds were identified by comparing with chemical reference substances. Dihydrotanshinone Ⅰ (16.98 µM), hydroxysafflor yellow A (84.57 µM), salvianolic acid A (76.62 µM) and cryptotanshinone (112.68 µM) were identified as acetylcholinesterase inhibitors from QLQX. Similarly, rosmarinic acid (62.29 µM), isochlorogenic acid A (17.95 µM), 4,5-dicaffeoylquinic acid (117.93 µM), danshensu (207.88 µM), salvianolic acid A (1.31 µM), 3,4-dicaffeoylquinic acid (91.71 µM), formononetin (67.26 µM), ginsenoside Rd (3.43 µM), ginsenoside Rb1 (26.37 µM) and ginsenoside F1 (18.79 µM) were discovered as α-glucosidase inhibitors. Notably, salvianolic acid A inhibited both acetylcholinesterase and α-glucosidase. The results of molecular docking indicated that hydrogen bonds, hydrophobic interactions and Pi-Pi T-shaped interactions were crucial for inhibiting acetylcholinesterase. Meanwhile, hydrogen bonds, hydrophobic interactions and Pi-Pi stacked interactions were significant in suppressing α-glucosidase. Conclusion: QLQX contains numerous acetylcholinesterase and α-glucosidase inhibitors, demonstrating its potential therapeutic benefits for Alzheimer's disease and diabetes. [ABSTRACT FROM AUTHOR]

In this study, a novel screening approach is presented, merging capillary electrophoresis analysis with an enzymatic assay employing immobilized α-glucosidase. A metal–organic framework composite membrane was devised for α-glucosidase immobilization. Employing polyvinylidene fluoride (PVDF) as the substrate material, it was functionalized with dopamine, creating a polydopamine composite layer. This layer acted as a covalent linker, anchoring Zn2+, which subsequently chelated with the organic ligand 2-ethylimidazole, leading to the self-assembly of a three-dimensional porous framework ZIF-8. This structure facilitated the in situ encapsulation of α-glucosidase. Characterization techniques including scanning electron microscopy, Fourier transform infrared-attenuated total reflectance spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction validated the composite material's structure. A thorough investigation of various parameters affecting immobilization was conducted. The immobilized α-glucosidase exhibited enhanced pH tolerance, thermal stability, and remarkable reusability, retaining 79.3% of its original activity over 10 cycles, with a batch-to-batch reproducibility of 5.9% (n = 5). Its Michaelis–Menten constant (Km) was determined to be 2.85 mM. Application of this immobilized enzyme in screening potential inhibitors from 13 traditional Chinese medicines revealed Sanguisorba radix as the most potent inhibitor. This study underscores the potential of this immobilized enzyme screening strategy for identifying enzyme inhibitors in traditional Chinese medicines. [ABSTRACT FROM AUTHOR]

Honokiol, a naturally occurring compound from Magnolia obovata Thunb., has many biological activities, but its anti-a-glucosidase activity is still unclear. Therefore, we determined its inhibitory effects against a-glucosidase. Activity assays showed that honokiol was a reversible mixed-type inhibitor of α-glucosidase, and its IC50 value was 317.11 ± 12.86 µM. Fluorescence results indicated that the binding of honokiol to α-glucosidase caused a reduction in α-glucosidase activity. 3D fluorescence and CD spectra results indicated that the binding of honokiol to α-glucosidase caused conformational change in α-glucosidase. Docking simulated the detailed interactions between honokiol and α-glucosidase, including hydrogen and hydrophobic bonds. All findings showed that honokiol could be used as a natural inhibitor to develop α-glucosidase agents. [ABSTRACT FROM AUTHOR]

Glycoside hydrolases (glycosidases) take part in myriad biological processes and are important therapeutic targets. Competitive and mechanism‐based inhibitors are useful tools to dissect their biological role and comprise a good starting point for drug discovery. The natural product, cyclophellitol, a mechanism‐based, covalent and irreversible retaining β‐glucosidase inhibitor has inspired the design of diverse α‐ and β‐glycosidase inhibitor and activity‐based probe scaffolds. Here, we sought to deepen our understanding of the structural and functional requirements of cyclophellitol‐type compounds for effective human α‐glucosidase inhibition. We synthesized a comprehensive set of α‐configured 1,2‐ and 1,5a‐cyclophellitol analogues bearing a variety of electrophilic traps. The inhibitory potency of these compounds was assessed towards both lysosomal and ER retaining α‐glucosidases. These studies revealed the 1,5a‐cyclophellitols to be the most potent retaining α‐glucosidase inhibitors, with the nature of the electrophile determining inhibitory mode of action (covalent or non‐covalent). DFT calculations support the ability of the 1,5a‐cyclophellitols, but not the 1,2‐congeners, to adopt conformations that mimic either the Michaelis complex or transition state of α‐glucosidases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and diabetes are non-communicable diseases with global impacts. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are suitable therapies for AD, while α-amylase and α-glucosidase inhibitors are employed as antidiabetic agents. Compounds were isolated from the medicinal plant Terminalia macroptera and evaluated for their AChE, BChE, α-amylase, and α-glucosidase inhibitions. From 1H and 13C NMR data, the compounds were identified as 3,3′-di-O-methyl ellagic acid (1), 3,3′,4′-tri-O-methyl ellagic acid-4-O-β-D-xylopyranoside (2), 3,3′,4′-tri-O-methyl ellagic acid-4-O-β-D-glucopyranoside (3), 3,3′-di-O-methyl ellagic acid-4-O-β-D-glucopyranoside (4), myricetin-3-O-rhamnoside (5), shikimic acid (6), arjungenin (7), terminolic acid (8), 24-deoxysericoside (9), arjunglucoside I (10), and chebuloside II (11). The derivatives of ellagic acid (1–4) showed moderate to good inhibition of cholinesterases, with the most potent being 3,3′-di-O-methyl ellagic acid, with IC50 values of 46.77 ± 0.90 µg/mL and 50.48 ± 1.10 µg/mL against AChE and BChE, respectively. The compounds exhibited potential inhibition of α-amylase and α-glucosidase, especially the phenolic compounds (1–5). Myricetin-3-O-rhamnoside had the highest α-amylase inhibition with an IC50 value of 65.17 ± 0.43 µg/mL compared to acarbose with an IC50 value of 32.25 ± 0.36 µg/mL. Two compounds, 3,3′-di-O-methyl ellagic acid (IC50 = 74.18 ± 0.29 µg/mL) and myricetin-3-O-rhamnoside (IC50 = 69.02 ± 0.65 µg/mL), were more active than the standard acarbose (IC50 = 87.70 ± 0.68 µg/mL) in the α-glucosidase assay. For α-glucosidase and α-amylase, the molecular docking results for 1–11 reveal that these compounds may fit well into the binding sites of the target enzymes, establishing stable complexes with negative binding energies in the range of −4.03 to −10.20 kcalmol−1. Though not all the compounds showed binding affinities with cholinesterases, some had negative binding energies, indicating that the inhibition was thermodynamically favorable. [ABSTRACT FROM AUTHOR]

A new series of quinoxaline‐sulfonamide derivatives 3–12 were synthesized using fragment‐based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline‐sulfonamide derivatives were evaluated for antidiabetic and anti‐Alzheimer's potential against α‐glucosidase, α‐amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α‐amylase and α‐glucosidase with inhibitory percentages between 24.34 ± 0.01%–63.09 ± 0.02% and 28.95 ± 0.04%–75.36 ± 0.01%, respectively. Surprisingly, bis‐sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α‐glucosidase and α‐amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α‐glucosidase and α‐amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide‐quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail. [ABSTRACT FROM AUTHOR]

Objective: Naphthoquinones are compounds that are common in nature which have biological activity depending on the attachment of new substituted groups. Methods: In the present study, the inhibition effects of newly synthesized naphthoquinones derivatives (I), (IIa–IId) on alpha-glucosidase, alpha-amylase, xanthine oxidase, and trypsin and antioxidant properties were investigated by in vitro studies. Results and Discussion: The synthesized compounds (IIb) (784.04 ± 79.95 µM) and (IId) (477.55 ± 1.18µM) compounds on alpha-glucosidase activity were found to have a lower IC50 value when compared to the positive control—acarbose (1628.48 ± 32.89 µM) as well as molecular docking results. Compound (IId) (690.45 ± 5.48 µM) had high 2,2-diphenyl-1-picrylhydrazil (DPPH) scavenging activity, with an IC50 value lower than that of the positive control butylated hydroxytoluene (BHT, 961.92 ± 6.41 µM). The results indicated that synthesized compounds had a dose-dependent inhibition effect on the enzymes. Conclusions: In the in vitro studies, compounds (IIb) and (IId) were strong alpha-glucosidase inhibitors as well as compound (IId) had high DPPH scavenging activity. [ABSTRACT FROM AUTHOR]

Objective: Postprandial hyperglycemia is considered an early sign of diabetes. Enzyme inhibitors, such as α-amylase and α-glucosidase inhibitors, are currently being studied as potential drugs for preventing postprandial hyperglycemia. Methods: In this study, we investigated the effects of four purified 7-hydroxycoumarine derivatives from Ferula assafoetida: umbelliprenin, farnesiferol A, farnesiferol C, and samarcandin. We evaluated cell toxicity using the MTT method and also examined glucose uptake and inhibition of α-amylase and α-glucosidase enzymes in vitro. Additionally, we conducted a molecular docking study to investigate the mechanism of enzyme inhibition. Results: The cell toxicity of the terpenoid coumarin derivatives (umbelliprenin, farnesiferol A, farnesiferol C, and samarcandin) on HepG2 cells was found to be approximately 28 to 37 µg/ml. The glucose uptake assay showed that these compounds (at a concentration of 25 µg/ml) were able to increase glucose consumption by HepG2 cells to a level comparable to that of the positive control (metformin at 50 µg/ml). Furthermore, umbelliprenin significantly inhibited the activity of α-amylase and α-glucosidase (by 35.07% and 4.98%, respectively). Molecular docking results indicated that umbelliprenin, with a farnesyl chain, had a more potent inhibitory effect. Conclusion: Our findings suggest that umbelliprenin may be a valuable compound for controlling postprandial hyperglycemia and diabetes. However, further in vivo studies and clinical trials are necessary to validate these effects. While this research offers potential for the development of more effective compounds with coumarin structures, further studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Yellowfin tuna (Thunnus albacares) is a valuable pelagic migratory fish with potential for aquaculture. Despite this, there is limited understanding of the biological and physiological characteristics of this species, particularly regarding sex differences in growth performance. The liver, a crucial organ for digestion and metabolism, plays a significant role in regulating fish growth. This study aimed to compare liver enzyme activities and transcriptome profiles between female and male yellowfin tuna to uncover the molecular mechanisms underlying difference between the sexes. The results revealed that female yellowfin tuna exhibited higher amylase and lipid metabolism enzyme activities, while male yellowfin tuna showed higher glucose-6-phosphate dehydrogenase and antioxidant enzyme activities. Additionally, through Illumina sequencing technology, the study generated 37.74 Gb of clean data and identified 36,482 unique genes (UniGenes) in the liver transcriptome. A total of 2542 differentially expressed genes were found, with enriched Gene Ontology terms and pathways related to metabolic processes, particularly lipid metabolism and transport. These findings suggest that female yellowfin tuna have superior digestive enzyme activities and lipid metabolism, while male yellowfin tuna excel in sugar metabolism, ATP production, and antioxidant defense. This study provides valuable insights into sex differences in yellowfin tuna and could aid in advancing full-cycle aquaculture practices for this species. [ABSTRACT FROM AUTHOR]

Alpinia officinarum is a commonly used spice with proven folk uses in various traditional medicines. In the current study, six compounds were isolated from its rhizomes, compounds 1–3 were identified as diarylheptanoids, while 4–6 were identified as flavonoids and phenolic acids. The isolated compounds were subjected to virtual screening against α-glucosidase, butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) enzymes to evaluate their potential antidiabetic and anti-Alzheimer's activities. Molecular docking and dynamics studies revealed that 3 exhibited a strong binding affinity to human a α- glucosidase crystal structure compared to acarbose. Furthermore, 2 and 5 demonstrated high potency against AChE. The virtual screening results were further supported by in vitro assays, which assessed the compounds' effects on α-glucosidase, cholinesterases, and their antioxidant activities. 5-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-phenylheptan-3-one (2) showed potent antioxidant effect in both ABTs and ORAC assays, while p-hydroxy cinnamic acid (6) was the most potent in the ORAC assay. In contrary, kaempferide (4) and galangin (5) showed the most potent effect in metal chelation assay. 5-Hydroxy-1,7-diphenylhepta-4,6-dien-3-one (3) and 6 revealed the most potent effect as α-glucosidase inhibitors where compound 3 showed more potent effect compared to acarbose. Galangin (5) revealed a higher selectivity to BChE, while 2 showed the most potent activity to (AChE). [ABSTRACT FROM AUTHOR]

Acacia nilotica L., also known as babul, belonging to the Fabaceae family and the Acacia genus, is typically used for ornamental purposes and also as a medicinal plant found in tropical and subtropical areas. This plant is a rich source of bioactive compounds. The current study aimed to elucidate the hypoglycemic, anti‐inflammatory, and neuroprotective potential of A. nilotica's crude methanolic extract. The results of the in vitro antidiabetic assay revealed that methanolic extract of A. nilotica inhibited the enzyme α‐glucosidase (IC50: 33 μg mL−1) and α‐amylase (IC50: 17 μg mL−1) in a dose‐dependent manner. While in the anticholinesterase enzyme inhibitory assay, maximum inhibition was shown by the extract against acetylcholinesterase (AChE) (637.01 μg mL−1) and butyrylcholinesterase (BChE) (491.98 μg mL−1), with the highest percent inhibition of 67.54% and 71.50% at 1000 μg mL−1, respectively. This inhibitory potential was lower as compared to the standard drug Galantamine that exhibited 82.43 and 89.50% inhibition at the same concentration, respectively. Moreover, the methanolic extract of A. nilotica also significantly inhibited the activities of cyclooxygenase 2 (COX‐2) and 5‐lipoxygenase (5‐LOX) in a concentration‐dependent manner. The percent inhibitory activity of 5‐LOX and COX‐2 ranged from 42.47% to 71.53% and 43.48% to 75.22%, respectively. Furthermore, in silico, in vivo, and clinical investigations must be planned to validate the above‐stated bioactivities of A. nilotica. [ABSTRACT FROM AUTHOR]

• Inhibiting alpha-glucosidase enzyme can help regulate blood sugar levels, making it an important target in the treatment of diabetes. • Phytochemicals are bioactive compounds found in plants; these phytochemicals possess significant potential for inhibiting the alpha-glucosidase enzyme. • The integrated approach allows for virtual screening of a wide range of phytochemicals, narrowing down the candidates for experimental validation. This is a cost-effective and efficient method for identifying potential drug leads. Alpha-glucosidase is a crucial enzyme involved in carbohydrate metabolism, and inhibiting its activity holds promise for treating Type 2 Diabetes Mellitus (T2DM). This study aimed to identify potential drugs that can selectively target alpha-glucosidase's essential enzyme, Maltase-glucoamylase, to discover potent antidiabetic compounds. A phytochemical library containing 2000 compounds from various plants was subjected to screening using a deep learning approach, molecular docking, ADMET, and DruliTo against the Maltase-glucoamylase enzyme. The compounds exhibiting strong binding affinity with the enzyme were further analyzed through Molecular Dynamics Simulation (MDS). MDS analysis, including (RMSD) Root Mean Square Deviation, Root Mean Square Fluctuation (RMSF), Radius of Gyration, Hydrogen-bond, and PCA, indicates that Carpaine, Pseudocarpaine, Pollinastanol, and Annosquamosin C have favorable interactions with alpha-glucosidase. Moreover, analysis of free binding energy substantiates the stability of these interactions, as evidenced by the binding energies of α-Glucosidase-Reference (-4.6 kJ/mol), α-Glucosidase-Pollinastaol (-4.7 kJ/mol), α-Glucosidase-Annosquamosoin C (-5.6 kJ/mol), α-Glucosidase-Pseudocarpaine (-8.0 kJ/mol), and α-Glucosidase-Carpaine (-10.2 kJ/mol). Based on these results, we conclude that these phytochemicals possess significant potential for inhibiting the alpha-glucosidase enzyme. The findings of this study suggest that these phytochemicals may exhibit promising inhibitory activity against α-Glucosidase and should be further investigated in vitro and in vivo experiments as potential natural resources for developing effective antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Multivalency represents an appealing option to modulate selectivity in enzyme inhibition and transform moderate glycosidase inhibitors into highly potent ones. The rational design of multivalent inhibitors is however challenging because global affinity enhancement relies on several interconnected local mechanistic events, whose relative impact is unknown. So far, the largest multivalent effects ever reported for a non‐polymeric glycosidase inhibitor have been obtained with cyclopeptoid‐based inhibitors of Jack bean α‐mannosidase (JBα‐man). Here, we report a structure‐activity relationship (SAR) study based on the top‐down deconstruction of best‐in‐class multivalent inhibitors. This approach provides a valuable tool to understand the complex interdependent mechanisms underpinning the inhibitory multivalent effect. Combining SAR experiments, binding stoichiometry assessments, thermodynamic modelling and atomistic simulations allowed us to establish the significant contribution of statistical rebinding mechanisms and the importance of several key parameters, including inhitope accessibility, topological restrictions, and electrostatic interactions. Our findings indicate that strong chelate‐binding, resulting from the formation of a cross‐linked complex between a multivalent inhibitor and two dimeric JBα‐man molecules, is not a sufficient condition to reach high levels of affinity enhancements. The deconstruction approach thus offers unique opportunities to better understand multivalent binding and provides important guidelines for the design of potent and selective multiheaded inhibitors. [ABSTRACT FROM AUTHOR]

Building upon a previously established (2+3)‐cycloaddition strategy, a series of N,N‐dialkylated aminocyclopentanes was synthesized using a partially protected eno‐furanose as the starting point. The resulting N‐methylisoxazolidine was subsequently transformed into the corresponding aminocyclopentane, which was further N‐alkylated, yielding a collection of compounds with potential as inhibitors and pharmacological chaperones of β‐d‐glucocerebrosidase. A comprehensive screening involving a range of biologically relevant glycosidases unveiled that these compounds exhibit remarkable potency and selectivity as inhibitors of human lysosomal β‐d‐glucocerebrosidase. However, none of these compounds exhibit significant activity enhancement of Morbus Gaucher related p.N409S/p.L483P mutant β‐d‐glucocerebrosidase. [ABSTRACT FROM AUTHOR]

In this study, we synthesized azepinodiazepine derivatives in high yields using multicomponent reactions of isatins, activated acetylenic compounds, alkyl bromides, methyl aziridine and ammonium acetate in the presence of Fe3O4/ZnO@MWCNT as a high-performance catalyst and teiethyl amine in water at room temperature. The Fe3O4/ZnO@MWCNT synthesizes using Petasites hybridus rhizome water extract as a green media and moderate base. Also, the catalytic activity of the green synthesized Fe3O4/ZnO@MWCNT MNCs was evaluated in the reduction of organic pollutants such as 4-nitrophenol (4-NP) in water at mild conditions. The results indicated that the biosynthesized NCs have very high and effective catalytic activity for organic pollutants within a few seconds. Investigation of the antioxidant ability of synthesized compounds using radical trapping of diphenyl-picrylhydrazine (DPPH) and ferric reduction power experiment is another purpose of this research. Also, the antimicrobial activity of some synthesized compounds was proved by employing the disk diffusion test on Gram-positive and Gram-negative bacteria. Also, to better understanding reaction mechanism density functional theory (DFT) based quantum chemical methods have been applied. This procedure has some benefits such as short reaction time, products with excellent yields, simple catalyst and product separation. Green chemistry is the use of a set of principles to reduce or eliminate the use or generation of unsafe materials in the design, fabrication and applications of chemical products. Among solvents, water is a green solvents and very suitable for performing organic reaction. The present procedure avoids the use of toxic solvent. Some representatives of this class of azaheterocycles are known as antiviral agents, glycosidase inhibitors, anticancer agents or antidiabetics. Therefore, in view of their medicinal relevance, an increasing number of synthetic methods have been described in recent years for the construction of highly substituted azepine derivatives. [ABSTRACT FROM AUTHOR]

Measuring glycosidase activity is important to monitor any aberrations in carbohydrate hydrolase activity, but also for the screening of potential glycosidase inhibitors. To this end, synthetic substrates are needed which provide an enzyme‐dependent read‐out upon hydrolysis by the glycosidase. Herein, we present two new routes for the synthesis of caged luminescent carbohydrates, which can be used for determining glycosidase activity with a luminescent reporter molecule. The substrates were validated with glycosidase and revealed a clear linear range and enzyme‐dependent signal upon the in situ generation of the luciferin moiety from the corresponding nitrile precursors. Besides, we showed that these compounds could directly be synthesized from unprotected glycosyl‐α‐fluorides in a two‐step procedure with yields up to 75 %. The intermediate methyl imidate appeared a key intermediate which also reacted with d‐cysteine to give the corresponding d‐luciferin substrate rendering this a highly attractive method for synthesizing glycosyl luciferins in good yields. [ABSTRACT FROM AUTHOR]

The hydroalcoholic roots' extracts of Plumbago indica L. and P. auriculata Lam. were studied for phenolic profiles using the HPLC technique and enzyme inhibitory activities using in-vitro and in -silico models. HPLC analyses of both extracts revealed the presence of fifteen and thirteen phenolic compounds for P. indica and P. auriculata , respectively. P. indica root extract contained Catechin (5321.63 µg/g) and Gallic acid (4616.29 µg/g) while P. auriculata root extract showed rutin (1505.46 µg/g) and ellagic acid (1390.72 µg/g) as the major compounds. The enzyme inhibitory assays showed that both Plumbago species have enzyme inhibition activities against all tested enzymes; acetylcholinesterase, butyrylcholinesterase, α-amylase, α-glucosidase, tyrosinase, and xanthine oxidase. The superior activity was accounted for by P. indica. with I.C. 50 values of 138.63, 25.69, 169.31, 90.31, 197.66, and 55.68 µg/ml while the inhibitory potential of P. auriculata was the lowest with I.C. 50 equal to 152.75, 36.32, 179.71, 103.71, 217.23, and 74.88 µg/ml, respectively for acetylcholinesterase, butyrylcholinesterase, α-amylase, α-glucosidase, tyrosinase, and xanthine oxidase. The docking studies showed promising results for certain compounds. These findings imply that these extracts have the potential to act as enzyme inhibitors for the treatment of disorders associated with them. [Display omitted] • Phenolic compounds were identified from the Plumbago species. • Both Plumbago species have enzyme inhibitory activities a by certain compounds. [ABSTRACT FROM AUTHOR]

In this study, we synthesized azepinooxazepine derivatives in high yields using multicomponent reactions of aniline, diethyl carbonate, alkyl bromides, activated acetylenic compounds, methyl aziridine and Fe3O4/ZnO@MWCNT as a high performance catalyst and teiethyl amine in water at room temperature. The catalytic activity of the green synthesized Fe3O4/ZnO@MWCNT MNCs was evaluated in the reduction of organic pollutants such as 4-nitrophenol (4-NP) in water at mild conditions. The results indicated that the biosynthesized NCs have very high and effective catalytic activity for organic pollutants within few seconds. Investigation of antioxidant ability of synthesized compounds using radical trapping of DPPH and ferric reduction power experiment is another purpose in this research. Also, the antimicrobial activity of some synthesized compounds proved by employing the disk diffusion test on Gram-positive and Gram-negative bacteria. Also, density functional theory (DFT) based quantum chemical methods have been applied for better understanding reaction mechanism. Green chemistry is the use of a set of principles to reduce or eliminate the use or generation of unsafe materials in the design, fabrication and applications of chemical products. Among solvents, water is a green solvents and very suitable for performing organic reaction. The present procedure avoids the use of toxic solvent. Some representatives of this class of azaheterocycles are known as antiviral agents, glycosidase inhibitors, anticancer agents or antidiabetics. Therefore, in view of their medicinal relevance, an increasing number of synthetic methods have been described in recent years for the construction of highly substituted azepine derivatives. [ABSTRACT FROM AUTHOR]

The present work describes the synthesis of new series of 5‐arylidene‐thiazolidine‐2,4‐dione, thieno[2,3‐d]pyrimidine‐6‐carboxylate derivatives 9 a–o. A variety of spectroscopic techniques like IR, 13CNMR, 1HNMR and LCMS were used to establish the presence of the every synthesized scaffold. The antioxidant activity of the target compounds has been studied by three different methods indicated the significant DPPH, NO and H2O2. Further, all the derivatives were evaluated for the in vitro antidiabetic potential against human pancreatic α‐amylase (PDB ID: 5NN3) and human lysosomal acid α‐glucosidase (PDB ID: 2QV4) enzymes followed by Molecular docking studies to ascertain the binding interactions of the compounds with the enzymes. The compounds 9 b and 9 g containing methoxy groups were found to exhibit potent antidiabetic and antioxidant activity. Therefore, it was rationalized that two privileged pharmacophores i. e. aryledenethiazolidine‐2,4‐dione and thieno[2,3‐d]pyrimidine‐6‐carboxylate assimilated hybrids, may be beneficial as lead template for the advance of future anti‐diabetic agents. Thus, benzylidenethiazolidine‐2,4‐dione and thieno[2,3‐d], the two preferred pharmacophores, were rationalized. Assimilation of ‐pyrimidine‐6‐carboxylate hybrids could be advantageous as a lead template for the development of new anti‐diabetic drugs. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is considered one of the major health diseases worldwide, one that requires immediate alternatives to allow treatments for DM to be more effective and less costly for patients and also for health-care systems. Recent approaches propose treatments for DM based on that; in addition to focusing on reducing hyperglycemia, they also consider multitargets, as in the case of plants. Among these, we find the plant known as chia to be highlighted, a crop native to Mexico and one cultivated in Mesoamerica from pre-Hispanic times. The present work contributes to the review of the antidiabetic effects of chia for the treatment of DM. The antidiabetic effects of chia are effective in different mechanisms involved in the complex pathogenesis of DM, including hypoglycemic, antioxidant, and anti-inflammatory mechanisms, and the inhibition of the enzymes α-glucosidase and α-amylase, as well as in the prevention of the risk of cardiovascular disease. The tests reviewed included 16 in vivo assays on rodent models, 13 clinical trials, and 4 in vitro tests. Furthermore, chia represents advantages over other natural products due to its availability and its acceptance and, in addition, as a component of the daily diet worldwide, especially due to its omega-3 fatty acids and its high concentration of dietary fiber. Thus, chia in the present work represents a source of antidiabetic agents that would perhaps be useful in novel clinical treatments. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effect of curcumin on the growth performance, slaughter performance, apparent nutrient digestibility, intestinal morphology, and digestive enzyme activity of meat rabbits. One hundred and sixty healthy weaned meat rabbits were randomly divided into four groups (forty replicates per group and one rabbit per replicate). The control group was fed a basal diet and the test groups (T1, T2 and T3) were fed diets supplemented with 50, 100 and 150 g/t curcumin in the basal diet, respectively. The study lasted for 28 days, including a pre-feeding period of 7 days and a formal trial period of 21 days. The results showed that diets supplemented with curcumin significantly increased rabbits' body weight gain and average daily feed intake; Apparent digestibility of energy, crude protein, crude fat, crude fibre, NDF and ADF; Jejunal villus height, the ratio of villus height to crypt depth; The activities of amylase and lipase in jejunal and caecal digesta and cellulase in caecal digesta; Caecal mucosal thickness, eviscerated dressing percentage, and dorsal and abdominal hair thickness (p <.05). Diets supplemented with curcumin significantly decreased rabbits' feed to gain ratio, jejunal crypt depth and thickness of the intestinal wall (p <.05). In conclusion, curcumin is a kind of valuable feed additive, which can improve the nutrient digestibility, growth performance, slaughter ratio and fur development of meat rabbits by improving digestive tract development and digestive enzyme activity. The appropriate dosage in the meat rabbit diet is 100 g/t. Dietary supplementation of curcumin improved the growth performance, gastrointestinal digestive enzyme activities and slaughter performance of meat rabbits. Dietary supplementation of curcumin increased the antioxidant capacity of meat rabbits. Curcumin could be used as a new kind of feed additive for meat rabbits. [ABSTRACT FROM AUTHOR]

The small molecule, isatin, is a well‐known reversible inhibitor of the monoamine oxidase (MAO) enzymes with IC50 values of 12.3 and 4.86 μM for MAO‐A and MAO‐B, respectively. While the interaction of isatin with MAO‐B has been characterized, only a few studies have explored structure–activity relationships (SARs) of MAO inhibition by isatin analogues. The current study therefore evaluated a series of 14 isatin analogues as in vitro inhibitors of human MAO‐A and MAO‐B. The results indicated good potency MAO inhibition for some isatin analogues with five compounds exhibiting IC50 < 1 μM. 4‐Chloroisatin (1b) and 5‐bromoisatin (1f) were the most potent inhibitors with IC50 values of 0.812 and 0.125 μM for MAO‐A and MAO‐B, respectively. These compounds were also found to be competitive inhibitors of MAO‐A and MAO‐B with Ki values of 0.311 and 0.033 μM, respectively. Among the SARs, it was interesting to note that C5‐substitution was particularly beneficial for MAO‐B inhibition. MAO inhibitors are established drugs for the treatment of neuropsychiatric and neurodegenerative disorders, while potential new roles in prostate cancer and cardiovascular disease are being investigated. [ABSTRACT FROM AUTHOR]

In this study, a novel series of sulfonate esters derived from 3‐hydroxyflavone was synthesized and their inhibitory effects on acetylcholinesterase (AChE), α‐glycosidase (AG), and carbonic anhydrase I and II (hCA I and II) enzymes were investigated using experimental and molecular docking analyses. The synthesis involved the reaction of 3‐hydroxyflavone with tosyl chloride, mesytl chloride, β‐naphthylsulfonyl chloride, and 8‐quinolinesulfonyl chloride. The characterization of each compound was confirmed by obtaining 1H NMR, 13C NMR and IR spectra. Furthermore, IC50 and Ki values for the synthesized compounds were calculated and compared to the clinical enzyme inhibitors. Our results showed that the synthesized compounds exhibited inhibition against the targeted enzymes, with Ki values ranging from 1.92 to 4.16 nM for AChE, 32.40 to 55.49 nM for AG, 9.45 to 65.53 nM for hCA I, and 76.62 to 163.33 nM for hCA II. The compound involved quinolinesulfonyl moiety demonstrated especially potent inhibition with IC50 values of 3.96 nM for AChE, 32.40 nM for AG, 9.50 nM for hCA I, and 76.62 nM for hCA II. The docking results aligned well with our experimental findings. The findings have promising implications for the development of novel inhibitors and drug discovery efforts in the future. [ABSTRACT FROM AUTHOR]

Glycosidases are ubiquitous enzymes that catalyze the hydrolysis of glycosidic linkages in oligosaccharides and glycoconjugates. These enzymes play a vital role in a wide variety of biological events, such as digestion of nutritional carbohydrates, lysosomal catabolism of glycoconjugates, and posttranslational modifications of glycoproteins. Abnormal glycosidase activities are associated with a variety of diseases, particularly cancer and lysosomal storage disorders. Owing to the physiological and pathological significance of glycosidases, the development of small molecules that target these enzymes is an active area in glycoscience and medicinal chemistry. Research efforts carried out thus far have led to the discovery of numerous glycosidase-targeting small molecules that have been utilized to elucidate biological processes as well as to develop effective chemotherapeutic agents. In this review, we describe the results of research studies reported since 2018, giving particular emphasis to the use of fluorescent probes for detection and imaging of glycosidases, activity-based probes for covalent labelling of these enzymes, glycosidase inhibitors, and glycosidase-activatable prodrugs. [ABSTRACT FROM AUTHOR]

We are reporting a novel series of thiosemicarbazone derivatives derived from isatin (1-6), structural determination, and investigation of the inhibitory properties against proliferative, carbonic anhydrase, and cholinesterase enzymes. The anti-proliferative effects of the compounds were measured by XTT assay against MCF-7 and MDA-MB-231 cancerous cell lines. Compound 3 showed significant cytotoxic effects on both MCF-7 and MDA-MB-231 cell lines, with IC50 values of 8.19 µM and 23.41 µM, respectively. In addition, the compounds (1-6) inhibited the hCA I and II, their Ki values 2.01 ± 0.35 - 21.55 ± 2.56 and 1.24 ± 0.33 - 25.03 ± 5.48 µM, respectively. AChE was also successfully inhibited by these compounds (1-6), with Ki values ranging from 40.37 ± 8.23 to 125.43 ± 24.93 µM. The best Ki values for 3, 6, and 4 for α-glycosidase were 564.35 ± 72.06, 594.38 ± 52.04, and 683.437 ± 66.58 µM, respectively. Binding affinities were determined to be -6.697 kcal/mol, -8.251 kcal/mol, -9.932 kcal/mol, and -4.946 kcal/mol for hCA I, hCA II, AChE, and _-glucosidase enzymes, respectively. These findings reveal that the formed compounds containing isatin moieties were crucial in the enzyme inhibition. [ABSTRACT FROM AUTHOR]

Oxidative stress, COX-2, LDHA and hyperglycemia are interlinked contributing pathways in the etiology, progression and metastasis of colon cancer. Additionally, dysregulated apoptosis in cells with genetic alternations leads to their progression in malignant transformation. Therefore, quinazolinones 3a–3h and 5a–5h were synthesized and evaluated as antioxidants, enzymes inhibitors and cytotoxic agents against LoVo and HCT-116 cells. Moreover, the most active cytotoxic derivatives were evaluated as apoptosis inducers. The results indicated that 3a, 3g and 5a were efficiently scavenged DPPH radicals with lowered IC50 values (mM) ranging from 0.165 ± 0.0057 to 0.191 ± 0.0099, as compared to 0.245 ± 0.0257 by BHT. Derivatives 3h, 5a and 5h were recognized as more potent dual inhibitors than quercetin against α-amylase and α-glucosidase, in addition to 3a, 3c, 3f and 5b–5f against α-amylase. Although none of the compounds demonstrated a higher efficiency than the reference inhibitors against COX-2 and LDHA, 3a and 3g were identified as the most active derivatives. Molecular docking studies were used to elucidate the binding affinities and binding interactions between the inhibitors and their target proteins. Compounds 3a and 3f showed cytotoxic activities, with IC50 values (µM) of 294.32 ± 8.41 and 383.5 ± 8.99 (LoVo), as well as 298.05 ± 13.26 and 323.59 ± 3.00 (HCT-116). The cytotoxicity mechanism of 3a and 3f could be attributed to the modulation of apoptosis regulators (Bax and Bcl-2), the activation of intrinsic and extrinsic apoptosis pathways via the upregulation of initiator caspases-8 and -9 as well as executioner caspase-3, and the arrest of LoVo and HCT-116 cell cycles in the G2/M and G1 phases, respectively. Lastly, the physicochemical, medicinal chemistry and ADMET properties of all compounds were predicted. [ABSTRACT FROM AUTHOR]

Enzymes are important catalysts in biochemical reactions with superior regio, stereo, and substrate selectivity. However, enzymatic reaction systems have drawbacks including product inhibition, difficulty recycling, and poor stability. Importantly, the rate of an enzyme catalyzed reaction diminishes rapidly due to product inhibition and substrate depletion, making it difficult for many enzymes to catalyze a reaction to completion. The outcome is a mixture of unreacted substrates being present in the final reaction, necessitating additional separation steps that increase costs. This study presents a microfluidic reactor for accelerating enzyme catalyzed reactions using a countercurrent design that continuously removes products and adds fresh substrate into the reaction, allowing enzymes to operate under better reaction conditions. It demonstrates that countercurrent flow accelerates enzymatic reactions in our system up to 36 % for horseradish peroxidase and 21 % for β‐glucosidase compared to cocurrent flow, and the resulting reaction solution contains highly pure product with minimal substrate contamination. [ABSTRACT FROM AUTHOR]

Diabetes treatment requires focused administration with quality systemic circulation to determine the optimal therapeutic window. Intestinal distribution through oral administration with nanoformulation provides several benefits. Therefore, the purpose of this study is to create plumbagin enclosed within niosomes using the quality by design (QbD) strategy for efficient penetration and increased bioavailability. The formulation and optimization of plumbagin-loaded niosomes (P-Ns-Opt) involved the use of a Box–Behnken Design. The particle size (PDI) and entrapment efficiency of the optimized P-Ns-Opt were 133.6 nm, 0.150, and 75.6%, respectively. TEM, DSC, and FTIR were used to analyze the morphology and compatibility of the optimized P-Ns-Opt. Studies conducted in vitro revealed a controlled release system. P-Ns-Opt's antioxidant activity, α-amylase, and α-glucosidase were evaluated, and the results revealed a dose-dependent efficacy with 60.68 ± 0.02%,90.69 ± 2.9%, and 88.43 ± 0.89%, respectively. In summary, the created P-Ns-Opt demonstrate remarkable potential for antidiabetic activity by inhibiting oxygen radicals, α-amylase, and α-glucosidase enzymes and are, therefore, a promising drug delivery nanocarrier in the management and treatment of diabetes. [ABSTRACT FROM AUTHOR]

Caesalpinia sappan (CS) has been commonly used in beverage and folk medicine in China and ASEAN countries because of its various therapeutic properties. Only the heartwood has long been used in traditional medicines due to the presence of high concentration of brazilin (one of the most important bioactive compounds), whereas the other parts are limited in use. Thus, this work aimed to investigate ways of utilizing other parts of CS. This information is important for further use of other CS parts to promote zero waste and hence sustainable resource utilization. Herein, the crude ethanolic (CEE) and crude aqueous (CAE) extracts from twelve parts of CS were evaluated for their biological activities for the first time. Our work demonstrates that not only the heartwood, but also other parts of CS exhibit interesting biological activities. CAE from heartwood of branches exhibits the highest antioxidant activity, which is higher than that of the positive control, butylated hydroxytoluene. CEE from florets shows the highest inhibitory effect against α-amylase, while CAE of barks shows better α-glucosidase inhibitory activity than the existing glucosidase inhibitor (acarbose). Molecular docking of brazilin (key bioactive compound) to both α-amylase and glucosidase can also confirm the tight binding of brazilin to α-glucosidase. [ABSTRACT FROM AUTHOR]

Ag/Fe3O4/TiO2/CuO@MWCNTs magnetic nanocomposites were synthesized by the Petasites hybridus rhizome water extract as green media and used for one-pot multicomponent reaction of isatins, electron deficient acetylenic compounds, α-haloketones, ammonium acetate, tert-butyl isocyanide and ethyl bromopyruvate in aqueous media at room temperature for the production of novel derivatives of oxazolopyrimidoazepines in excellent yields. The synthesized oxazolopyrimidoazepines have OH and NH functional groups that have acidic hydrogen and show high antioxidant activity. Moreover, reduction of organic pollutants such 4-nitrophenol (4-NP) was performed by synthesized Ag/Fe3O4/TiO2/CuO@MWCNTs in water at room temperature. The outcomes showed this catalyst was decreased organic pollutants in few seconds. The employed process for the production of oxazolopyrimidoazepines has some benefits such as short time of reactions, excellent efficiency of product, easy separation of catalyst and products. HIGHLIGHTS Green chemistry is the use of a set of principles to reduce or eliminate the use or generation of unsafe materials in the design, fabrication and applications of chemical products. Among solvents, water is a green solvents and very suitable for performing organic reaction. The present procedure avoids the use of toxic solvent. Some representatives of this class of azaheterocycles are known as antiviral agents, glycosidase inhibitors, anticancer agents or antidiabetics. Therefore, in view of their medicinal relevance, an increasing number of synthetic methods have been described in recent years for the construction of highly substituted azepine derivatives. [ABSTRACT FROM AUTHOR]

Thirteen new derivatives of the phthalimide‐1,2,3‐triazole‐N‐phenylacetamide hybrids were synthesized via simple chemical reactions. These hybrids were evaluated for their inhibitory potential against α‐glucosidase in vitro and in silico. Among these thirteen derivatives, seven compounds showed excellent inhibition against studied enzyme (IC50 values=1.30−31.7 μM) as compared to positive control acarbose (IC50 value=750.1 μM) and among them, compound with 2,4‐dichloro substituent on the phenyl ring of N‐phenylacetamide moiety was identified as the most potent inhibitor against α‐glucosidase. This compound was almost 577‐fold more active than acarbose. Kinetic study on the most potent compound demonstrated that this compound is a competitive α‐glucosidase inhibitor. To understand the interaction mode, stability, and flexibility of the most potent compounds, molecular docking and molecular dynamics studies were conducted. Furthermore, the drug‐likeness, pharmacokinetic, and toxicity properties of the title compounds were predicted by in silico studies. [ABSTRACT FROM AUTHOR]

Bacillus megaterium tyrosinase (Bm TYR) has been proven an applicable biocatalyst in the ortho -hydroxylation of flavonoids, which usually possess higher antioxidant activity than their precursors. With a predicted data mining approach (PDMA), putative novel bioactive flavonoids from known precursors may be good candidates for biotransformation by Bm TYR. Two flavonoid precursors (loureirin A and loureirin B) were confirmed via this approach, which are the commercial constituents of the Chinese medicine dragon's blood. These two flavonoids were then biotransformed by Bm TYR for validation. The results found two novel flavonoids (3′-hydroxyloureirin A and 3′-hydroxyloureirin B), which gained 2.5 and 1.6 times of the antioxidant activity of ascorbic acid, respectively. In addition, all four flavonoids—loureirin A, loureirin B, and the two 3′-hydroxyl derivatives—possessed 4–22 times the anti- α -glucosidase activity of acarbose, a clinical anti-diabetes drug. A further kinetic analysis revealed that the inhibition mode of the four α -glucosidase inhibitors was non-competitive, and their kinetic constants (K i values) were 64.3 ± 2.5 μM, 308.7 ± 10.4 μM, 69.4 ± 2.8 μM, and 325.3 ± 12.6 μM, respectively. The high antioxidant and anti- α -glucosidase activity suggest that the two novel flavonoids have potential future applications in pharmacology and biotechnology. [Display omitted] • A predicted data mining approach (PDMA) was developed for finding novel biotransformated-compounds. • Two novel flavonoids, 3′-hydroxyloureirin A and 3′-hydroxyloureirin B, were identified. • The two novel flavonoids gain potent antioxidant and anti- α -glucosidase activities. [ABSTRACT FROM AUTHOR]

Graptophyllum pictum is a tropical plant noticeable for its variegated leaves and exploited for various medicinal purposes. In this study, seven compounds, including three furanolabdane diterpenoids, i.e., Hypopurin E, Hypopurin A and Hypopurin B, as well as with Lupeol, β-sitosterol 3-O-β-d-glucopyranoside, stigmasterol 3-O-β-d-glucopyranoside and a mixture of β-sitosterol and stigmasterol, were isolated from G. pictum, and their structures were deduced from ESI-TOF-MS, HR-ESI-TOF-MS, 1D and 2D NMR experiments. The compounds were evaluated for their anticholinesterase activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BchE), as well as their antidiabetic potential through inhibition of α-glucosidase and α-amylase. For AChE inhibition, no sample had IC50 within tested concentrations, though the most potent was Hypopurin A, which had a percentage inhibition of 40.18 ± 0.75%, compared to 85.91 ± 0.58% for galantamine, at 100 µg/mL. BChE was more susceptible to the leaves extract (IC50 = 58.21 ± 0.65 µg/mL), stem extract (IC50 = 67.05 ± 0.82 µg/mL), Hypopurin A (IC50 = 58.00 ± 0.90 µg/mL), Hypopurin B (IC50 = 67.05 ± 0.92 µg/mL) and Hypopurin E (IC50 = 86.90 ± 0.76 µg/mL). In the antidiabetic assay, the furanolabdane diterpenoids, lupeol and the extracts had moderate to good activities. Against α-glucosidase, lupeol, Hypopurin E, Hypopurin A and Hypopurin B had appreciable activities but the leaves (IC50 = 48.90 ± 0.17 µg/mL) and stem (IC50 = 45.61 ± 0.56 µg/mL) extracts were more active than the pure compounds. In the α-amylase assay, stem extract (IC50 = 64.47 ± 0.78 µg/mL), Hypopurin A (IC50 = 60.68 ± 0.55 µg/mL) and Hypopurin B (IC50 = 69.51 ± 1.30 µg/mL) had moderate activities compared to the standard acarbose (IC50 = 32.25 ± 0.36 µg/mL). Molecular docking was performed to determine the binding modes and free binding energies of Hypopurin E, Hypopurin A and Hypopurin B in relation to the enzymes and decipher the structure–activity relationship. The results indicated that G. pictum and its compounds could, in general, be used in the development of therapies for Alzheimer's disease and diabetes. [ABSTRACT FROM AUTHOR]

Background: A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a–o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase. Methods: The 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted. Results: All new derivatives 11a–o (IC50 values = 6.31 ± 0.03–49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound. Conclusion: According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

Herein, various N′-substituted benzylidene benzohydrazide-1,2,3-triazoles were designed, synthesized, and screened for their inhibitory activity toward α-glucosidase. The structure of derivatives was confirmed using 1H- and 13C-NMR, FTIR, Mass spectrometry, and elemental analysis. All derivatives exhibited good inhibition with IC50 values in the range of 0.01 to 648.90 µM, compared with acarbose as the positive control (IC50 = 752.10 µM). Among them, compounds 7a and 7h showed significant potency with IC50 values of 0.02 and 0.01 µM, respectively. The kinetic study revealed that they are noncompetitive inhibitors toward α-glucosidase. Also, fluorescence quenching was used to investigate the interaction of three inhibitors 7a, 7d, and 7h, with α-glucosidase. Accordingly, the binding constants, the number of binding sites, and values of thermodynamic parameters were determined for the interaction of candidate compounds toward the enzyme. Finally, the in silico cavity detection plus molecular docking was performed to find the allosteric site and key interactions between synthesized compounds and the target enzyme. [ABSTRACT FROM AUTHOR]

This study examines the possibility of directly producing and utilizing useful substances in the intestines of animals using anaerobic bacteria that can grow in the intestines of animals. A facultative anaerobe producing a large amount of α-glucosidase inhibitor was isolated from hay and identified and named Bacillus coagulans CC. The main compound of α-glucosidase inhibitor produced by Bacillus coagulans CC was identified as 1-deoxynojirimycin. α-glucosidase inhibitor activity was confirmed in the intestinal contents and feces of mice orally administered with spores of this strain, and it was confirmed that this strain could efficiently reach the intestines, proliferate, and produce α-glucosidase inhibitors. As a result of administering Bacillus coagulans CC to mice at 109 cells per 1 kg body weight of spores for 8 weeks, the high-carbohydrate diet and the high-fat diet showed a 5% lower weight gain compared to the non-administrated group. At this point, in the spore-administered group, a decrease was observed in both the visceral and subcutaneous fat layers of the abdomen and thorax in both high-carbohydrate and high-fat diet groups compared to the non-administered group on computed tomography. The results of this study show that α-glucosidase inhibitors produced in the intestine by specific strains can work efficiently. [ABSTRACT FROM AUTHOR]

The most prevalent subtype of diabetes is Type 2 Diabetes Mellitus which results from an abnormal postprandial increase in blood glucose. Inhibition of the carbohydrate-hydrolysing enzymes (alpha-glucosidase and alpha-amylase) in the human digestive organs can control blood glucose levels, making it an important strategy in the management of Type 2 Diabetes Mellitus. A majority of the oral synthetic drugs which have been developed to treat Type 2 Diabetes Mellitus are expensive and have undesirable side effects. As a result, plant-derived remedies have become preferred alternatives as they are easily available, affordable and less harmful. Angustine (1) the major constituent in Nauclea subdita (Korth.) Steud., and (E)-labda-8(17),12-dien-15,16-dial (2) and zerumin A (3) of Alpinia pahangensis Ridley were evaluated for their α-glucosidase inhibitory activity. (E)-Labda-8(17),12-dien-15,16-dial (2) (IC50 = 39.7 µM) was identified as the most potent inhibitor among all three, followed by angustine (1) (IC50 = 48.1 µM) and zerumin A (3) (IC50 = 53.3 µM). Enzyme kinetic studies indicated that angustine (1) was a mixed-type inhibitor, while (E)-labda-8(17),12-dien-15,16-dial (2), and zerumin A (3) were non-competitive inhibitors. Molecular docking and molecular dynamics (MD) simulation studies were performed to predict the key interactions between the ligands and the target protein, 1AGM (complex of acarbose with glucoamylase from Aspergillus awamori). The results of the study of binding interaction energy suggested that angustine (1) has the potential to be used as a natural drug lead in the treatment of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Insect pest control is one of the major issues facing the agriculture sector because of the need for new agrochemicals and biocontrol agents that are environmentally friendly, economically affordable, and safe for human health. Spodoptera frugiperda (fall armyworm) is one of the insect pests that causes huge damage to various crops around the globe due to its generalist nature. In the present study, three selected Embelia ribes Burm F (Myrsinaceae) constituents, which include embelin, 5-O-methylembelin, and vilangin; one semi-synthetic compound (potassium embelate); three synthetic compounds, namely coenzyme Q10, dopaquinone, and idebenone; and two reference compounds (azadirachtin and amitraz) were assessed on the docking behavior of S. frugiperda (beta glycosidase and caspase-1. The docking studies showed that coenzyme Q10 exhibited the highest binding energies (-130.61 and -434.56 kcal. mol-1) for the target enzymes S. frugiperda (beta glycosidase and caspase-1, respectively). Thus, the present investigation provides new knowledge in understanding Embelia ribes Burm F (Myrsinaceae) constituents as possible inhibitors against S. frugiperda (beta glycosidase and caspase-1) enzyme activities. Furthermore, the present work can help to develop new insecticides and pesticides against S. frugiperda and other related insect pests. [ABSTRACT FROM AUTHOR]

Inhibition of intestinal α‐glucosidase (αGS), a crucial enzyme in carbohydrate digestion, is an effective therapeutic approach for diabetes mellitus treatment. The C‐glycosylflavonoids (CGFs) are natural compounds with antioxidant, antidiabetic, and anti‐inflammatory activities. The present work seeks an alternative compound among CGFs that can control the blood glucose level by inhibiting αGS enzyme activity. Therefore, ten CGFs were selected and carried out the docking to αGS. The docking outcomes proposed that among selected CGFs, the orientin compound can successfully interact with the key residues of Asp215, Glu277, Asp352, Arg442, and Arg446. Of them, the orientin compound with docking energy of −6.11 Kcal/mol, was subsequently subjected to molecular dynamics simulation (MDs), and in vitro investigation. MDs results indicated that orientin formed a stable complex with αGS enzyme. We also performed molecular mechanics generalized Born and surface area (MM/GBSA) free energy calculation manner on all chosen CGFs along with miglitol as reference. The IC50 value of orientin for αGS inhibition with competitive mode was found to be 0.13 mg/ml. The results highlight that orientin can be considered as a possible compound in treating DM via αGS inhibition. However, further in vitro and in vivo analyses are required to confirm this claim. [ABSTRACT FROM AUTHOR]

Suitably configured allyl ethers of unsaturated cyclitols act as substrates of β‐glycosidases, reacting via allylic cation transition states. Incorporation of halogens at the vinylic position of these carbasugars, along with an activated leaving group, generates potent inactivators of β‐glycosidases. Enzymatic turnover of these halogenated cyclitols (F, Cl, Br) displayed a counter‐intuitive trend wherein the most electronegative substituents yielded the most labile pseudo‐glycosidic linkages. Structures of complexes with the Sulfolobus β‐glucosidase revealed similar enzyme‐ligand interactions to those seen in complexes with a 2‐fluorosugar inhibitor, the lone exception being displacement of tyrosine 322 from the active site by the halogen. Mutation of Y322 to Y322F largely abolished glycosidase activity, consistent with lost interactions at O5, but minimally affected (7‐fold) rates of carbasugar hydrolysis, yielding a more selective enzyme for unsaturated cyclitol ether hydrolysis. [ABSTRACT FROM AUTHOR]

Polygoni Cuspidati Rhizoma et Radix (PCR), the rhizome and root of Polygonum cuspidatum Sieb. et Zucc., has been used as an herbal medicine for a long time. In this study, the ultrafiltration combined with high performance liquid chromatography (UF-HPLC) method was developed to screen tyrosinase (TYR), α-glucosidase (α-GLU), and xanthine oxidase (XOD) inhibitors from PCR. Firstly, the inhibitory activity of 50% methanol PCR extract on TYR, α-GLU, XOD, and acetylcholinesterase (ACHE) was tested. The extract showed a good inhibition on the enzymes, except for ACHE. Therefore, UF-HPLC experiments were carried out to screen TYR, α-GLU, and XOD inhibitors from PCR extract. Seven potential bioactive components were discovered, including methylgallate (1), 1,6-di-O-galloyl-D-glucose (2), polydatin-4′-O-D-glucoside (3), resveratrol-4′-O-D-glucoside (4), polydatin (5), malonyl glucoside resveratrol (6), and resveratrol-5-O-D-glucoside (7). Most of them were found as enzyme inhibitors from PCR for the first time, except polydatin (5), which had been reported as an α-GLUI in PCR in the literature. Finally, molecular docking analysis was applied to validate the interactions of these seven potential active components with the enzymes. Compounds 1–7 were proven as TYR inhibitors, compounds 2, 4–7 were identified as XOD inhibitors, and compounds 4–6 were confirmed as α-GLU inhibitors. In short, the current study provides a good reference for the screening of enzyme inhibitors through UF-HPLC, and provides scientific data for future studies of PCR. [ABSTRACT FROM AUTHOR]

Simple Summary: Hyphantria cunea is a cosmopolitan quarantine pest that can sustain on a wide range of host plants. However, the role of the digestive physiology of H. cunea larvae in regulating its multi-host adaptation has not been reported. Herein, we found that α-amylase and trypsin played an important role in nutrient metabolism and host adaptation of H. cunea. Furthermore, H. cunea larvae had highly adaptable compensatory mechanisms for digestion in response to insect digestive enzyme inhibitors. The findings reveal that digestive physiology mediates the multi-host adaptation of H. cunea larvae. Digestive physiology mediates the adaptation of phytophagous insects to host plants. In this study, the digestive characteristics of Hyphantria cunea larvae feeding preferences on different host plants were investigated. The results showed that the body weight, food utilization, and nutrient contents of H. cunea larvae feeding on the high-preference host plants were significantly higher than those feeding on the low-preference host plants. However, the activity of larval digestive enzymes in different host plants presented an opposite trend, as higher α-amylase or trypsin activity was observed in the group feeding on the low-preference host plants than that feeding on the high-preference host plants. Upon treatment of leaves with α-amylase and trypsin inhibitors, the body weight, food intake, food utilization rate, and food conversion rate of H. cunea larvae significantly decreased in all host plant groups. Furthermore, the H. cunea comprised highly adaptable compensatory mechanisms of digestion involving digestive enzymes and nutrient metabolism in response to digestive enzyme inhibitors. Taken together, digestive physiology mediates the adaptation of H. cunea to multiple host plants, and the compensatory effect of digestive physiology is an important counter-defense strategy implemented by H. cunea to resist plant defense factors, especially the insect digestive enzyme inhibitors. [ABSTRACT FROM AUTHOR]

Cyclophellitol aziridines have found wide application as mechanism‐based, covalent, and irreversible inhibitors of retaining glycosidases. These compounds, like their parent compound, cyclophellitol (a natural product retaining β‐glucosidase inactivator), make use of the mechanism of action of retaining glycosidases, which process their substrate through the formation of a transient covalent intermediate. In contrast, inverting glycosidases, the other main family of glycosyl hydrolases, do not employ such a covalent intermediate, and, as a consequence, useful scaffolds for mechanism‐based inhibitor design have yet to be discovered. In this work, we explore chemistries that allow for the construction of cyclitol aziridines with the aziridine electrophile attached in an exocyclic fashion, more distal from the anomeric carbon – thus putatively closer to an inverting glycosidase active site nucleophile. The developed chemistries have allowed for the synthesis of a focused library of differently N‐substituted, α‐and β‐glucopyranose configured cyclitol aziridines for future evaluation as inhibitors or inactivators of α‐and β‐glucosidases alike. [ABSTRACT FROM AUTHOR]

Green synthesis of nanoparticles is becoming a method of choice for biological research due to its environmentally benign outcomes, stability and ease of synthesis. In this study, silver nanoparticles (AgNPs) were synthesized using stem (S-AgNPs), root (R-AgNPs) and mixture of stem and root (RS-AgNPs) of Delphinium uncinatum. The synthesized nanoparticles were characterized by standardized techniques and evaluated for their antioxidant, enzyme inhibition, cytotoxic and antimicrobial potentials. The AgNPs exhibited efficient antioxidant activities and considerable enzyme inhibition potential against alpha amylase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. S-AgNPs showed strong cytotoxicity against human hepato-cellular carcinoma cells (HepG2) and high enzyme inhibitory effect (IC50 values 27.5μg/ml for AChE and 22.60 μg/ml for BChE) compared to R-AgNPs and RS-AgNPs. RS-AgNPs showed significant inhibition of Klebsiella pneumoniae and Aspergillus flavus and exhibited higher biocompatibility (<2% hemolysis) in human red blood cells hemolytic assays. The present study showed that biologically synthesized AgNPs using the extract of various parts of D. uncinatum have strong antioxidant and cytotoxic potentials. [ABSTRACT FROM AUTHOR]

Several researchers have demonstrated the health and pharmacological properties of carvacrol and p-cymene, monoterpenes of aromatic plants. This study investigated these compounds' possible anti-cholinesterase, anti-α-amylase, and neuroprotective effects. We evaluated the anti-acetylcholinesterase and anti-α-amylase activities at different concentrations of the compounds. The maximum non-toxic dose of carvacrol and p-cymene against SH-SY5Y neuroblastoma cells was determined using an MTT assay. The neuroprotective effects of the compounds were evaluated on H2O2-induced stress in SH-SY5Y cells, studying the expression of caspase-3 using Western blotting assays. Carvacrol showed inhibitory activities against acetylcholinesterase (IC50 = 3.8 µg/mL) and butyrylcholinesterase (IC50 = 32.7 µg/mL). Instead, the anti-α-amylase activity of carvacrol resulted in an IC50 value of 171.2 μg/mL After a pre-treatment with the maximum non-toxic dose of carvacrol and p-cymene, the expression of caspase-3 was reduced compared to cells treated with H2O2 alone. Carvacrol and p-cymene showed in vitro anti-enzymatic properties, and may act as neuroprotective agents against oxidative stress. Further studies are necessary to elucidate their possible use as coadjutants in preventing and treating AD in diabetic patients. [ABSTRACT FROM AUTHOR]