RESUMO
BACKGROUND: The increasing prevalence of diabetes and the side effects associated with current medications necessitate the development of novel candidate drugs targeting alpha-glucosidase as a potential treatment option. METHODS: This study employed computer-aided drug design techniques to identify potential alpha-glucosidase inhibitors from the PubChem database. Molecular docking was used to evaluate 81,197 compounds, narrowing the set for further analysis and providing insights into ligand-target interactions. An ADMET study assessed the pharmacokinetic properties of these compounds, including absorption, distribution, metabolism, excretion, and toxicity. Molecular dynamics simulations validated the docking results. RESULTS: 9 compounds were identified as potential candidate drugs based on their ability to form stable complexes with alpha-glucosidase and their favorable pharmacokinetic profiles, three of these compounds were subjected to the molecular dynamics, which showed stability throughout the entire 100 ns simulation. CONCLUSION: These findings suggest promising new alpha-glucosidase inhibitors for diabetes treatment. Further validation through in vitro and in vivo studies is recommended to confirm their efficacy and safety.
Assuntos
Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Triazóis , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Triazóis/química , Triazóis/farmacologia , alfa-Glucosidases/metabolismo , alfa-Glucosidases/química , Humanos , Simulação por Computador , Desenho de FármacosRESUMO
The chemical constituents in the ethanol extract of Viburnum utile were isolated by column chromatography with D101 macroporous resin, silica gel, and Sephadex LH-20. Their structures were identified by spectroscopic techniques such as NMR and MS. All the compounds were evaluated for the inhibitory activities against α-glucosidase. Sixteen compounds were obtained and identified as viburnumide A(1), vitamin E(2), α-amyrin(3), α-tocoquinone(4), narjatamanin B(5), ethyl caffeate(6), naringenin(7), apigenin(8), ethyl ß-D-ribo-hex-3-ulopyranoside(9), trans-p-hydroxycinnamic acid(10), amentoflavone(11), apigenin-7-O-ß-D-glucoside(12), luteolin-7-O-ß-D-glucoside(13), henryoside(14), ursolic acid(15), and 2α-hydroxy-oleanolic acid(16). Among them, compound 1 was a new compound, and compounds 2-16 were isolated from V. utile for the first time. The inhibitory activity(IC_(50) of 4.0 µmol·L~(-1)) of compound 11 against α-glucosidase was comparable to that of the positive control acarbose(IC_(50) of 2.3 µmol·L~(-1)).
Assuntos
Inibidores de Glicosídeo Hidrolases , Viburnum , alfa-Glucosidases , Viburnum/química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , alfa-Glucosidases/química , Estrutura Molecular , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
Diabetes Mellitus (DM) is linked to various factors causing cardiovascular diseases, with uncontrolled postprandial hyperglycemia being a direct contributor. α-Glucosidase inhibitors (AGIs) aid in reducing postprandial hyperglycemia, potentially mitigating cardiovascular risks. In order to synthesize novel chemical scaffolds with possible α-glucosidase inhibition activity, a series of novel soritin sulfonamide derivatives were synthesized. The soritin hydrazide was treated with various aryl sulfonyl chlorides to obtain targeted compounds (1-16). Findings suggested that all compounds have better α-glucosidase inhibition compared to standard drugs, acarbose (2187.00 ± 1.25 µM) and 1-deoxynojirimycin (334.90 ± 1.10 µM), with IC50 values ranging from 3.81 ± 1.67 µM to 265.40 ± 1.58 µM. The most potent analog was Compound 13, a trichloro phenyl substituted compound, with IC50 value of 3.81 ± 1.67 µM. Structure-activity relationship (SAR) showed that introducing an additional chlorine group into the parent nucleus increases the potency. The docking studies validated that Compound 13 established hydrogen bonds with the active site residues Asp214, Glu276, and Asp349, while being further stabilized by hydrophobic interactions, providing an explanation for its high potency.
Assuntos
Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , Sulfonamidas , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo , Humanos , Domínio Catalítico , Ligação de HidrogênioRESUMO
This study investigated the proximate composition and inhibitory potential of hot water and ethanolic extracts of the pulp, peel and whole fruit of green banana (Musa sapientum) on α-amylase and α-glucosidase. Bioactive compounds were identified using GC-MS analysis. In addition, the cytotoxic effect on human gingival fibroblast (hGF) was evaluated using the sulphorhodamine B (SRB) assay. The results showed that the peel of green banana had the highest amount of ash (10.05%), fat (2.83%), protein (3.64%) and total dietary fibre (36.62%). The carbohydrate content of the whole fruit (81.79%) and pulp (81.50%) was higher than that of the peel (71.90%). The moisture content of the pulp (13.08%) was higher than that of the peel (11.58%) and whole fruit (11.30%). The ethanolic green banana peel extract showed a good inhibitory effect of α-amylase and α-glucosidase with the concentration necessary for 50% inhibition (IC50) of 0.512 and 0.100 mg·mL-1, respectively. The α-glucosidase inhibitory effect of the ethanolic green banana peel extract and the hot water green banana peel extract was not significantly different from that of acarbose (IC50 0.108 mg·mL-1). GC-MS analysis of the ethanolic green banana peel extract revealed fatty acids and fatty acid ester (9-octadecenamide (Z), octadecanamide and other compounds). The ethanolic peel extract exhibits a significant noncytotoxicity effect on hGF cells at concentrations ranging from 0.0001 to 1.0 mg·mL-1.
Assuntos
Inibidores de Glicosídeo Hidrolases , Musa , Extratos Vegetais , alfa-Amilases , alfa-Glucosidases , Musa/química , alfa-Amilases/antagonistas & inibidores , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Inibidores de Glicosídeo Hidrolases/farmacologia , alfa-Glucosidases/metabolismo , Humanos , Frutas/química , Pós , Cromatografia Gasosa-Espectrometria de Massas , Fibroblastos/efeitos dos fármacosRESUMO
Lupins, and other legumes, have attained international interest due to their reported remarkable health benefits. Currently, the seed coats are discarded as waste or animal feed. The research presented here summarizes the potential for incorporating the seed coats into 'whole grain' foods. We aimed to identify metabolites found in the seed coats of nine commercial Australian cultivars of lupin (Lupinus angustifolius and L. albus species), and to evaluate and compare their functional, nutritional, antioxidant, and antidiabetic properties, along with in silico exploration of mechanisms of action for selected identified secondary metabolites. The seed coats were found to contain 79 to 90% dietary fibers and substantial quantity of essential macrometals. LC-QTOF MS-based, untargeted bioactive metabolite profiling explored a total of 673 chemical entities, and identified 63 bioactive secondary metabolites including: biophenols, unsaturated fatty acids, triterpenoids, alkaloids, and dietary prebiotics (insoluble fibers). The seed coats from these nine cultivars show substantial antioxidant activity. The cultivars of L. angustifolius inhibit α-amylase and α-glucosidase significantly in vitro. Moreover, in silico docking and dynamic simulation along with ADME/T analysis suggest that quercetin 3-methyl ether and 8-C-methylquercetin 3-methyl ether as molecules, novel in lupin seed coats, are responsible for the α-amylase and α-glucosidase inhibition. The findings indicated that lupin seed coats might be beneficial food components, rather than be discarded as 'mill waste'.
Assuntos
Antioxidantes , Hipoglicemiantes , Lupinus , Sementes , Antioxidantes/análise , Sementes/química , Lupinus/química , Hipoglicemiantes/análise , Simulação por Computador , Fibras na Dieta/análise , Valor Nutritivo , Austrália , alfa-Amilases/metabolismo , alfa-Amilases/antagonistas & inibidores , Cromatografia Líquida/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Glicosídeo Hidrolases/farmacologia , Espectrometria de Massas/métodosRESUMO
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.
Assuntos
Agricultura , Inibidores Enzimáticos , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Agricultura/métodos , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/uso terapêutico , Inibidores de Glicosídeo Hidrolases/farmacologiaRESUMO
A diminutive chemical library of acyl thiotriazinoindole (ATTI) based bioactive scaffolds was synthesized, instigated by taking the economical starting material Isatin, through a series of five steps. Isatin was first nitrated followed by the attachment of pentyl moiety via nucleophilic substitution reaction. The obtained compound was reacted with thiosemicarbazide to obtain thiosemicarbazone derivative, which was eventually cyclized using basic conditions in water as solvent. Finally, the reported series was obtained through reaction of nitrated thiotriazinoindole moiety with differently substituted phenacyl bromides. The synthesized compounds were characterized using NMR spectroscopy and elemental analysis. Finally, the synthesized motifs were scrutinized for their potential to impede urease, α-glucosidase, DPPH, and α-amylase. Compound 5 h with para cyano group manifested the most pivotal biological activity among all, displaying IC50 values of 29.7 ± 0.8, 20.5 ± 0.5 and 36.8 ± 3.9 µM against urease, α-glucosidase, and DPPH assay, respectively. Simultaneously, for α-amylase compound 5 g possessing a p-CH3 at phenyl ring unfolded as most active, with calculated IC50 values 90.3 ± 1.1 µM. The scaffolds were additionally gauged for their antifungal and antibacterial activity. Among the tested strains, 5d having bromo as substituent exhibited the most potent antibacterial activity, while it also demonstrated the highest potency against Aspergillus fumigatus. Other derivatives 5b, 5e, 5i, and 5j also exhibited dual inhibition against both antibacterial and antifungal strains. The interaction pattern of derivatives clearly displayed their SAR, and their docking scores were correlated with their IC50 values. In molecular docking studies, the importance of interactions like hydrogen bonding was further asserted. The electronic factors of various substituents engendered variety of interactions between the ligands and targets implying their importance in the structures of the synthesized heterocyclic scaffolds. To conclude, the synthesized compounds had satisfactory biological activity against various important targets. Further studies are therefore encouraged by attachment of different substitutions in the structure at various positions to enhance the activity of these compounds.
Assuntos
Antioxidantes , Simulação de Acoplamento Molecular , Urease , alfa-Amilases , alfa-Glucosidases , Urease/antagonistas & inibidores , Urease/química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Testes de Sensibilidade MicrobianaRESUMO
Pueraria lobata (Willd.) Ohwi is a traditional medicinal herb that has been extensively used in Chinese medicine for various therapeutic purposes. In this study, twelve chemical constituents were isolated from the roots of P. lobata, comprising three puerosides (compounds 1-3), six alkaloids (compounds 4-9), and three additional compounds (compounds 10-12). Notably, compound 1 (4R-pueroside B) was identified as a novel compound. The structures of all compounds were elucidated using a range of spectroscopic techniques, including CD spectroscopy for the first-time determination of the absolute configurations of pueroside B isomers (compounds 1 and 2). Enzyme inhibition assays revealed that, with the exception of compound 2, all isolated compounds exhibited varying degrees of α-glucosidase and α-amylase inhibitory activity. Remarkably, compound 12 demonstrated IC50 values of 23.25 µM for α-glucosidase inhibition and 27.05 µM for α-amylase inhibition, which are superior to those of the positive control, acarbose (27.05 µM and 36.68 µM, respectively). Additionally, compound 11 exhibited inhibitory activity against α-glucosidase and α-amylase comparable to the positive control, acarbose. Molecular docking studies indicated that compound 12 interacts with the active sites of the enzymes via hydrogen bonds, van der Waals forces, and hydrophobic interactions, which likely contribute to their inhibitory effects. These findings suggest that the chemical constituents of P. lobata could be potential natural sources of α-amylase and α-glucosidase inhibitors, with compound 12 being particularly promising for further investigation.
Assuntos
Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , Raízes de Plantas , Pueraria , alfa-Amilases , alfa-Glucosidases , Pueraria/química , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , Raízes de Plantas/química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , alfa-Glucosidases/metabolismo , alfa-Glucosidases/química , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , IsomerismoRESUMO
Background: Sapota, Manilkara zapota L., are tasty, juicy, and nutrient-rich fruits, and likewise used for several medicinal uses. Methods: The current study represents an integrated metabolites profiling of sapota fruits pulp via GC/MS and UPLC/MS, alongside assessment of antioxidant capacity, pancreatic lipase (PL), and α-glucosidase enzymes inhibitory effects. Results: GC/MS analysis of silylated primary polar metabolites led to the identification of 68 compounds belonging to sugars (74%), sugar acids (18.27%), and sugar alcohols (7%) mediating the fruit sweetness. Headspace SPME-GC/MS analysis led to the detection of 17 volatile compounds belonging to nitrogenous compounds (72%), ethers (7.8%), terpenes (7.6%), and aldehydes (5.8%). Non-polar metabolites profiling by HR-UPLC/MS/MS-based Global Natural Products Social (GNPS) molecular networking led to the assignment of 31 peaks, with several novel sphingolipids and fatty acyl amides reported for the first time. Total phenolic content was estimated at 6.79 ± 0.12 mg gallic acid equivalent/gram extract (GAE/g extract), but no flavonoids were detected. The antioxidant capacities of fruit were at 1.62 ± 0.2, 1.49 ± 0.11, and 3.58 ± 0.14 mg Trolox equivalent/gram extract (TE/g extract) via DPPH, ABTS, and FRAP assays, respectively. In vitro enzyme inhibition assays revealed a considerable pancreatic lipase inhibition effect (IC50 = 2.2 ± 0.25 mg/mL), whereas no inhibitory effect towards α-glucosidase enzyme was detected. This study provides better insight into sapota fruit's flavor, nutritional, and secondary metabolites composition mediating for its sensory and health attributes.
Assuntos
Antioxidantes , Frutas , Lipase , Lipase/antagonistas & inibidores , Lipase/metabolismo , Frutas/química , Frutas/metabolismo , Antioxidantes/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , alfa-Glucosidases/metabolismo , Espectrometria de Massas em Tandem/métodosRESUMO
To find potential α-glucosidase inhibitors, a series of 2ß-acetoxyferuginol derivatives containing cinnamic acid (WXC-1 â¼ 25) were synthesized and investigated their biological activity. All derivatives (WXC-1 â¼ 25) displayed better inhibitory activity (IC50 values: 7.56 ± 1.35 â¼ 25.63 ± 1.72 µM) compared to acarbose (IC50 vaule: 564.28 ± 48.68 µM). In particularly, WXC-25 with 4-hydroxycinnamic acid section showed the best inhibitory activity (IC50 vaule: 2.02 ± 0.14 µM), â¼75-fold stronger than acarbose. Kinetics results suggested WXC-25 being one reversible non-competition inhibitors. Fluorescence quenching results indicated that WXC-25 quenched the fluorescence of α-glucosidase in a static manner. 3D fluorescence spectra results indicated that WXC-25 treatment could cause the conformation changes of α-glucosidase. Moreover, molecular docking simulated the detailed interaction of WXC25 with α-glucosidase.
Assuntos
Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , alfa-Glucosidases/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Cinamatos/química , Cinamatos/farmacologia , Cinamatos/síntese química , CinéticaRESUMO
Ripened pu-erh tea is known to have beneficial hypoglycemic properties. However, it remains unclear whether the bioactive peptides produced during fermentation are also related to hypoglycemic potential. This study aimed to identify hypoglycemic peptides in ripened pu-erh tea and to elucidate their bioactive mechanisms using physicochemical property prediction, molecular docking, molecular dynamics simulations, and cell experiments. Thirteen peptides were identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Among them, AADTDYRFS (AS-9) and AGDGTPYVR (AR-9) exhibited high α-glucosidase inhibitory activity, with half-maximal inhibitory concentration (IC50) values of 0.820 and 3.942 mg/mL, respectively. Molecular docking and dynamics simulations revealed that hydrogen bonding, hydrophobic interactions, and van der Waals forces assist peptides AS-9 and AR-9 in forming stable and tight complexes with α-glucosidase. An insulin-resistance (IR)-HepG2 cell model was established. AS-9 was non-toxic to IR-HepG2 cells and significantly increased the glucose consumption capacity, hexokinase, and pyruvate kinase activities of IR-HepG2 cells (p < 0.05). AS-9 alleviated glucose metabolism disorders and ameliorated IR by activating the IRS-1/PI3K/Akt signaling pathway and increasing the expression levels of MDM2, IRS-1, Akt, PI3K, GLUT4, and GSK3ß genes. In addition, no hemolysis of mice red blood cells red blood cells occurred at concentrations below 1 mg/mL. This work first explored hypoglycemic peptides in ripened pu-erh tea, providing novel insights for enhancing its functional value.
Assuntos
Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Simulação de Acoplamento Molecular , Peptídeos , Chá , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Animais , Chá/química , Humanos , Células Hep G2 , Peptídeos/química , Peptídeos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Camundongos , Simulação de Dinâmica Molecular , Resistência à Insulina , Transdução de Sinais/efeitos dos fármacos , Proteínas Substratos do Receptor de Insulina/metabolismo , Espectrometria de Massas em Tandem , alfa-Glucosidases/metabolismo , FermentaçãoRESUMO
Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC50 = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC50 = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.
A small, focused library comprising 8 novel compounds was synthesised using a series of substituted quinoxaline sulfonohydrazide derivatives.All synthesised compounds were tested against phospholipase A2 (sPLA2) and α-glucosidase enzymes.The compounds exhibited activities against α-glucosidase and were potent at nanomolar concentrations against sPLA2 isozymes.Structure-based molecular modelling was employed to rationalise the SAR of the compounds.
Assuntos
Diabetes Mellitus Tipo 2 , Relação Dose-Resposta a Droga , Hipoglicemiantes , Quinoxalinas , alfa-Glucosidases , Quinoxalinas/farmacologia , Quinoxalinas/química , Quinoxalinas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Relação Estrutura-Atividade , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Estrutura Molecular , alfa-Glucosidases/metabolismo , Modelos Moleculares , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento MolecularRESUMO
Calendula officinalis L. has numerous health-promoting properties due to the presence of a large number of lipophilic compounds. Their effective delivery to the body requires the use of an appropriate technique such as emulsification. So, the main purpose of this study was to understand how the profile of lipophilic compounds from pot marigold and the pro-health potential are shaped by different types of protein, oil, and drying techniques in o/w nanoemulsion. To obtain this, the profiles of carotenoid compounds and tocols were measured. Additionally, antioxidant potential and the ability to inhibit α-amylase and α-glucosidase were measured. Pea protein emulsion exhibited a higher final content of carotenoid compounds (23.72-39.74 mg/100 g), whereas those with whey protein had stronger α-amylase inhibition (487.70 mg/mL). The predominant compounds in the studied nanoemulsions were ß-carotene (between 19% and 40%), followed by α-tocopherol/γ-tocopherol. The type of proteins shaped the health-promoting properties and determined the content of health-promoting compounds.
Assuntos
Antioxidantes , Calendula , Carotenoides , Emulsões , Tocoferóis , Tocotrienóis , Emulsões/química , Carotenoides/química , Carotenoides/isolamento & purificação , Antioxidantes/química , Antioxidantes/farmacologia , Tocoferóis/química , Tocotrienóis/química , Calendula/química , alfa-Amilases/antagonistas & inibidores , Extratos Vegetais/química , Proteínas do Soro do Leite/química , Nanopartículas/química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologiaRESUMO
Different natural products derived from plants have long been utilized as traditional herbal remedies to treat a variety of ailments and these substances have inspired the design, discovery and development of new pharmaceuticals. Andrographis paniculata is an annual plant that is frequently grown for therapeutic purposes in Southeast Asian countries. The A. paniculata Nees is an Indonesian natural plant that is thought to have antioxidant, anti-diabetic, anti-inflammatory and anti-hyperlipidemic properties. In this study, ultrasonic-assisted extraction (UAE) was used to optimize extraction conditions by varying time and amplitude. Furthermore, the UAE extract was evaluated for antioxidant activity utilizing 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), iron reducing antioxidant power (FRAP), and copper ion reducing antioxidant capacity (CUPRAC), as well as its anti-diabetic potential via α-glucosidase inhibition. Based on antioxidant activity with an IC50 value of 73.71 ±0.28, extract B (extraction time 35 minutes and amplitude 65%) was considered to have optimum conditions for extraction. In addition, it was found that extract A. paniculata (extraction time 30 minutes and amplitude 60%) showed the most active inhibitory activity against α-glucosidase, with an IC50 value of 0.87 ±0.003. The A. paniculata ethanolic leaf extract exhibits antioxidant and anti-diabetic properties.
Assuntos
Andrographis , Antioxidantes , Inibidores de Glicosídeo Hidrolases , Extratos Vegetais , Folhas de Planta , Andrographis/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificação , Antioxidantes/química , Folhas de Planta/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Hipoglicemiantes/farmacologia , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/química , alfa-Glucosidases/metabolismo , Ondas Ultrassônicas , Compostos de Bifenilo/químicaRESUMO
Magnolia bark is a traditional Chinese medicine used for hypoglycaemia. With the widespread use of Magnolia bark, its resources are facing a serious shortage. To address this issue, a strategy based on high-coverage mass spectrometry (HCMS) and multidimensional chemical-biological analysis (MCBA) was proposed for the comprehensive exploration of Magnolia officinalis which is the main source of Magnolia bark. The strategy is divided into three main steps. In the first step, the stem bark, stem xylem, root bark, root xylem, leaf and rootlet of Magnolia officinalis were comprehensively analyzed using high-coverage mass spectrometry. In the second step, multivariate statistical analysis was used to explore the heterogeneity of the six parts and detect differential chemical components. In the third step, a combination of experimental screening and molecular docking was used to explore α-glucosidase inhibitors from Magnolia officinalis. Multidimensional chemical-biological analysis (MCBA) of Magnolia officinalis was achieved by combining the last two steps. Finally, a total of 103 compounds were identified from the whole plant of Magnolia officinalis. Differential components of stem bark, stem xylem, leaf, root bark, root xylem and rootlet were systematically revealed. A pair of positional isomers, namely magnolol and honokiol, were found to be α-glucosidase inhibitors. The activity of their combination is superior to that of each single compound, indicating that magnolol and honokiol are in a synergistic relationship. This strategy contributes to comprehensive exploitation of functional plants and effective alleviation of resource shortage. This study also provides a research paradigm for other similar traditional Chinese medicinal plants.
Assuntos
Magnolia , Espectrometria de Massas , Magnolia/química , Espectrometria de Massas/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Simulação de Acoplamento Molecular , Plantas Medicinais/química , Inibidores de Glicosídeo Hidrolases/análise , Inibidores de Glicosídeo Hidrolases/químicaRESUMO
Pholidota cantonensis Rolfe is an edible medicinal plant in the genus Pholidota of the family Orchidaceae. This plant is used to prepare medicated food in China and has been reported to possess anti-α-glucosidase activity. To date, little is known about the active substances responsible for the observed anti-α-glucosidase activity. In the present study, we aimed to screen and characterize the α-glucosidase inhibitory fraction of P. cantonensis using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) analysis and molecular docking. As a result, the 50% ethanol fraction obtained from D101 macroporous adsorption resin column chromatography (D50 fraction) had the highest total phenol content (353.83 ± 6.06 mg GAE/g) and the most prominent α-glucosidase inhibitory activity (IC50 = 30.01 ± 7.30 µg/mL). Forty-five compounds were identified from the D50 fraction by using UPLC-Q-TOF-MS/MS analysis. Molecular docking results showed that six main constituents, namely, crepidatin, 2,7-dihydroxy-4-methoxyl-9,10-dihydrophenylene, 4,4',5,6-tetrahydroxystilbene, 4,7-dihydroxy-2-methoxyl-9,10-dihydrophenylene, (-)-lariciresinol, and thunalbene, in the D50 fraction occupied the catalytic sites of α-glucosidase through strong hydrophobic interactions, hydrogen bonding, and other patterns. The binding energies were between - 29.95 and - 11.41 kJ/mol, indicating good binding between the tested compounds and α-glucosidase. The active ingredients responsible for the α-glucosidase inhibitory activity may include phenanthrenes, stilbenes, dibenzyls, and lignans. The D50 fraction has potential value for developing innovative drugs for the prevention and treatment of diabetes mellitus (DM) and is worthy of in-depth research.
Assuntos
Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , Orchidaceae , Plantas Medicinais , Espectrometria de Massas em Tandem , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Espectrometria de Massas em Tandem/métodos , Plantas Medicinais/química , alfa-Glucosidases/metabolismo , Orchidaceae/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Fenóis/análise , Fenóis/farmacologiaRESUMO
Reactions with allyl-, acetyl-, and phenylisothiocyanate have been studied on the basis of 3-amino-4,6-dimethylpyridine-2(1H)-one, 3-amino-4-phenylpyridine-2-one, and 3-amino-4-(thiophene-2-yl)pyridine-2(1H)-one (benzoyl-)isothiocyanates, and the corresponding thioureide derivatives 8-11a-c were obtained. Twelve thiourea derivatives were obtained and studied for their anti-diabetic activity against the enzyme α-glucosidase in comparison with the standard drug acarbose. The comparison drug acarbose inhibits the activity of α-glucosidase at a concentration of 15 mM by 46.1% (IC50 for acarbose is 11.96 mM). According to the results of the conducted studies, it was shown that alkyl and phenyl thiourea derivatives 8,9a-c, in contrast to their acetyl-(benzoyl) derivatives and 10,11a-c, show high antidiabetic activity. Thus, 1-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9a has the highest inhibitory activity against the enzyme α-glucosidase, exceeding the activity of the comparison drug acarbose, which inhibits the activity of α-glucosidase by 56.6% at a concentration of 15 mm (IC50 = 9,77 mM). 1-(6-methyl-2-oxo 4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9c has inhibitory activity against the enzyme α-glucosidase, comparable to the comparison drug acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mm per 41.2% (IC50 = 12,94 mM). Compounds 8a, 8b, and 9b showed inhibitory activity against the enzyme α-glucosidase, with a lower activity compared to acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mM by 23.3%, 26.9%, and 35.2%, respectively. The IC50 against α-glucosidase for compounds 8a, 8b, and 9b was found to be 16.64 mM, 19.79 mM, and 21.79 mM, respectively. The other compounds 8c, 10a, 10b, 10c, 11a, 11b, and 11c did not show inhibitory activity against α-glucosidase. Thus, the newly synthesized derivatives of thiourea based on 3-aminopyridine-2(1H)-ones are promising candidates for the further modification and study of their potential anti-diabetic activity. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models.
Assuntos
Inibidores de Glicosídeo Hidrolases , Tioureia , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/síntese química , Tioureia/química , Tioureia/farmacologia , Tioureia/análogos & derivados , Tioureia/síntese química , alfa-Glucosidases/metabolismo , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Estrutura Molecular , Aminopiridinas/química , Aminopiridinas/farmacologia , Aminopiridinas/síntese químicaRESUMO
α-glucosidase, a pharmacological target for type 2 diabetes mellitus (T2DM), is present in the intestinal brush border membrane and catalyzes the hydrolysis of sugar linkages during carbohydrate digestion. Since α-glucosidase inhibitors (AGIs) modulate intestinal metabolism, they may influence oxidative stress and glycolysis inhibition, potentially addressing intestinal dysfunction associated with T2DM. Herein, we report on a study of an ortho-carbonyl substituted hydroquinone series, whose members differ only in the number and position of methyl groups on a common scaffold, on radical-scavenging activities (ORAC assay) and correlate them with some parameters obtained by density functional theory (DFT) analysis. These compounds' effect on enzymatic activity, their molecular modeling on α-glucosidase, and their impact on the mitochondrial respiration and glycolysis of the intestinal Caco-2 cell line were evaluated. Three groups of compounds, according their effects on the Caco-2 cells metabolism, were characterized: group A (compounds 2, 3, 5, 8, 9, and 10) reduces the glycolysis, group B (compounds 1 and 6) reduces the basal mitochondrial oxygen consumption rate (OCR) and increases the extracellular acidification rate (ECAR), suggesting that it induces a metabolic remodeling toward glycolysis, and group C (compounds 4 and 7) increases the glycolysis lacking effect on OCR. Compounds 5 and 10 were more potent as α-glucosidase inhibitors (AGIs) than acarbose, a well-known AGI with clinical use. Moreover, compound 5 was an OCR/ECAR inhibitor, and compound 10 was a dual agent, increasing the proton leak-driven OCR and inhibiting the maximal electron transport flux. Additionally, menadione-induced ROS production was prevented by compound 5 in Caco-2 cells. These results reveal that slight structural variations in a hydroquinone scaffold led to diverse antioxidant capability, α-glucosidase inhibition, and the regulation of mitochondrial bioenergetics in Caco-2 cells, which may be useful in the design of new drugs for T2DM and metabolic syndrome.
Assuntos
Antioxidantes , Metabolismo Energético , Inibidores de Glicosídeo Hidrolases , Hidroquinonas , alfa-Glucosidases , Humanos , Células CACO-2 , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/metabolismo , Hidroquinonas/farmacologia , Hidroquinonas/química , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacosRESUMO
In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure-activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.
Assuntos
4-Hidroxicumarinas , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/síntese química , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo , alfa-Glucosidases/química , 4-Hidroxicumarinas/química , 4-Hidroxicumarinas/farmacologia , 4-Hidroxicumarinas/síntese química , Simulação por Computador , Domínio Catalítico , Simulação de Dinâmica MolecularRESUMO
The subcritical water extraction of Undaria pinnatifida (blade, sporophyll, and root) was evaluated to determine its chemical properties and biological activities. The extraction was conducted at 180 °C and 3 MPa. Root extracts exhibited the highest phenolic content (43.32 ± 0.19 mg phloroglucinol/g) and flavonoid content (31.54 ± 1.63 mg quercetin/g). Sporophyll extracts had the highest total sugar, reducing sugar, and protein content, with 97.35 ± 4.23 mg glucose/g, 56.44 ± 3.10 mg glucose/g, and 84.93 ± 2.82 mg bovine serum albumin (BSA)/g, respectively. The sporophyll contained the highest fucose (41.99%) and mannose (10.37%), whereas the blade had the highest galactose (48.57%) and glucose (17.27%) content. Sporophyll had the highest sulfate content (7.76%). Key compounds included sorbitol, glycerol, L-fucose, and palmitic acid. Root extracts contained the highest antioxidant activity, with IC50 values of 1.51 mg/mL (DPPH), 3.31 mg/mL (ABTS+), and 2.23 mg/mL (FRAP). The root extract exhibited significant α-glucosidase inhibitory activity with an IC50 of 5.07 mg/mL, indicating strong antidiabetic potential. The blade extract showed notable antihypertensive activity with an IC50 of 0.62 mg/mL. Hence, subcritical water extraction to obtain bioactive compounds from U. pinnatifida, supporting their use in functional foods, cosmetics, and pharmaceuticals is highlighted. This study uniquely demonstrates the variation in bioactive compound composition and bioactivities across different parts of U. pinnatifida, providing deeper insights. Significant correlations between chemical properties and biological activities emphasize the use of U. pinnatifida extracts for chronic conditions.