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1.
Food Chem ; 399: 133999, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36037688

RESUMO

Melastoma dodecandrum Lour. (MDL) extracts have shown potent α-glucosidase inhibitory activity, suggesting MDL might be a good source of α-glucosidase inhibitors. The aim of the study was to identify compounds in MDL extracts with α-glucosidase inhibitory activities and evaluate their effect on postprandial blood glucose as well as elucidating the underlying mechanisms of inhibition. A total of 34 polyphenols were identified in MDL fruits, among which 10 anthocyanins and three proanthocyanidin derivatives were discovered for the first time. Dosing mice with MDL extracts (100 mg/kg body weight, by gavage) was associated with a significantly decrease in postprandial blood glucose concentrations after oral administration of maltose. The most potent α-glucosidase inhibitor was identified as casuarictin (IC50 of 0.21 µg/mL). Casuarictin bound competitively to α-glucosidase, occupying not only the catalytic site but also forming strong hydrogen bonds with α-glucosidase residues. Therefore, casuarictin derived from MDL fruits might be used as novel α-glucosidase inhibitor in functional foods or other dietary products.


Assuntos
Inibidores de Glicosídeo Hidrolases , Melastomataceae , Animais , Antocianinas , Glicemia/metabolismo , Frutas/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Melastomataceae/metabolismo , Camundongos , Extratos Vegetais/química , alfa-Glucosidases/metabolismo
2.
Food Chem ; 401: 134156, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36099826

RESUMO

Influences of conventional thermal and innovative non-thermal extraction methods on the physicochemical characteristics and properties of pectic polysaccharides from Choerospondias axillaris peels were investigated. Results showed that ultrasound-assisted extracted polysaccharides (UP) had a heterogeneous nature with lower molecular weight (127.7 kDa) and lower neutral sugar content (35.1%) but higher contents of protein (4.8%) and phenolic compounds (5.1%) than those of polysaccharides extracted by hot water (HP). Additionally, the monosaccharide composition results showed that glucose (77.8%) was the most abundant monosaccharide in HP, while arabinose (67.1%) was the most abundant monosaccharide in UP. The ultrasound significantly induced the degradation of polysaccharide chains but reduced the thermal degradation of phenolics. Finally, we found that UP had higher apparent viscosity, interfacial, emulsifying and antioxidant activity but lower α-glucosidase inhibition activity than those of HP. The results indicated that we could obtain polysaccharides with different functional and biological properties by using different extraction methods.


Assuntos
Anacardiaceae , Pectinas , Pectinas/química , Antioxidantes/química , alfa-Glucosidases/metabolismo , Arabinose , Anacardiaceae/química , Polissacarídeos/química , Monossacarídeos , Água/química , Fenóis , Glucose
3.
Spectrochim Acta A Mol Biomol Spectrosc ; 285: 121806, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36108405

RESUMO

Curcumin (bis-α,ß-unsaturated ß-diketone) plays an important role in the prevention of numerous diseases, including diabetes. Curcumin, as an enzyme inhibitor, has ideal structural properties including hydrophobic nature, flexible backbone, and several available hydrogen bond (H-bond) donors and acceptors. In this study, curcumin-fused aldohexose derivatives 3(a-c) were synthesized and used as influential agents in the treatment of diabetes with inhibitory properties against two carbohydrate-hydrolyzing enzymes α-glucosidase (α-Gls) and α-amylase (α-Amy) which are known to be significant therapeutic targets for the reduction of postprandial hyperglycemia. These compounds were isolated, purified, and then spectrally characterized via FT-IR, Mass, 1H, and 13C NMR, which strongly confirmed the targeted product's formation. Also, their inhibitory properties against α-Gls and α-Amy were evaluated spectroscopically. The Results indicated that all compounds strongly inhibited α-Amy and α-Gls by mixed and competitive mechanisms, respectively. The intrinsic fluorescence of α-Amy was quenched by the interaction with compounds 1 and 3b through a dynamic quenching mechanism, and the 1 and 3b/α-Amy complexes were spontaneously formed, mainly driven by the hydrophobic interaction and hydrogen bonding. Fourier transform infrared spectra (FT-IR) comprehensively verified that the binding of compounds 1 and 3b to α-Amy would change the conformation and microenvironment of α-Amy, thereby inhibiting the enzyme activity. Docking and molecular dynamics (MD) simulations showed that all compounds interacted with amino acid residues located in the active pocket site of the proteins. In vivo studies confirmed the plasma glucose diminution after the administration of compound 3b to Wistar rats. Accordingly, the results of the current work may prompt the scientific communities to investigate the possibility of compound 3b application in the clinic.


Assuntos
Curcumina , Diabetes Mellitus , Ratos , Animais , Hipoglicemiantes/química , Curcumina/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Ratos Wistar , alfa-Glucosidases/metabolismo , alfa-Amilases/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Glicosídeo Hidrolases/química
4.
Int J Mol Sci ; 23(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36362322

RESUMO

The incidence of diabetes mellitus (DM), one of the most common chronic metabolic disorders, has increased dramatically over the past decade and has resulted in higher rates of morbidity and mortality worldwide. The enzyme, α-Glucosidase (α-GLy), is considered a therapeutic target for the treatment of type 2 DM. Herein, we synthesized arylidene, heterocyclic, cyanoetoxy- and propargylated derivatives of quinopimaric acid (levopimaric acid diene adduct with p-benzoquinone) 1-50 and, first, evaluated their ability to inhibit α-GLy. Among the tested compounds, quinopimaric acid 1, 2,3-dihydroquinopimaric acid 8 and its amide and heterocyclic derivatives 9, 30, 33, 39, 44, with IC50 values of 35.57-65.98 µM, emerged as being good inhibitors of α-GLy. Arylidene 1ß-hydroxy and 1ß,13α-epoxy methyl dihydroquinopimarate derivatives 6, 7, 26-29, thiadiazole 32, 1a,4a-dehydroquinopimaric acid 40 and its indole, nitrile and propargyl hybrids 35-38, 42, 45, 48, and 50 showed excellent inhibitory activities. The most active compounds 38, 45, 48, and 50 displayed IC50 values of 0.15 to 0.68 µM, being 1206 to 266 more active than acarbose (IC50 of 181.02 µM). Kinetic analysis revealed the most active diterpene indole with an alkyne substituent 45 as a competitive inhibitor with Ki of 50.45 µM. Molecular modeling supported this finding and suggested that the indole core plays a key role in the binding. Compound 45 also has favorable pharmacokinetic and safety properties, according to the computational ADMET profiling. The results suggested that quinopimaric acid derivatives should be considered as potential candidates for novel alternative therapies in the treatment of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Diterpenos , Humanos , alfa-Glucosidases/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cinética , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Indóis/uso terapêutico , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Estrutura Molecular
5.
Org Biomol Chem ; 20(45): 8962-8976, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36326164

RESUMO

Due to the growth in the incidence of diabetes mellitus throughout the world, the urgency in the search for new safe and effective inhibitors of α-amylase and α-glucosidase is increasing. In this work, we attempted to carry out studies on the synthesis, modification and comprehensive computer and biological research of new derivatives of monothiooxamides. It was shown that monothiooxamides based on 3-aminopyridin-2(1H)-ones enter into transamidation reactions with hydrazine hydrate to form the corresponding thiohydrazides. Furthermore, under the action of chloroacetyl chloride and succinic anhydride, these thiohydrazides are cyclized into conjugated 1,3,4-thiadiazole derivatives. The possible biological activity of the obtained products was evaluated by molecular docking using the AutoDock Vina program. Compounds 7a and 8b showed higher binding affinities for selected target proteins compared to the known anti-diabetic drugs acarbose and TAK-875. The obtained new derivatives of 1,3,4-thiadiazole showed sufficiently high values of inhibitory activity in the in vitro test against the enzymes α-amylase and α-glucosidase as well as sufficiently low IC50 values (for 8b 122.2 µM), which is 8 times less than the value for the reference drug acarbose (998.3 µM). All synthesized derivatives of monothiooxamides 5-8(a-c) showed no cytotoxic properties at physiological concentrations in the MTT test in human neonatal dermal fibroblasts. Moreover, some compounds (6a-c, 7a-c, 8b,c) showed pronounced cytoprotective activity. Thus, the compounds 5-8(a-c) synthesized by us, both according to the results of computer calculations and in vitro biological screening, showed their potential antidiabetic activity and high prospects for further in-depth studies, including in vivo studies.


Assuntos
Tiadiazóis , alfa-Glucosidases , Humanos , Acarbose , alfa-Amilases/química , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiadiazóis/farmacologia , Tiadiazóis/química
6.
Future Med Chem ; 14(21): 1507-1526, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36268762

RESUMO

Background: To discover novel lead molecules against diabetes, Alzheimer's disease and oxidative stress, a library of arylated pyrazole-fused pyran derivatives, 1-20, were synthesized in a one-pot reaction. Materials & methods:1H-NMR spectroscopic and electron ionization mass spectrometry techniques were used to characterize the synthetic hybrid molecules 1-20. Analogs were screened against four indispensable therapeutic targets, including α-amylase, α-glucosidase, acetylcholinesterase and butyrylcholinesterase enzymes. Results: Except for derivatives 17 and 18, all other compounds exhibited varying degrees of inhibitory activities against target enzymes. The kinetic studies revealed that the synthetic molecules followed a competitive-type mode of inhibition for α-amylase and acetylcholinesterase enzymes, as well as a non-competitive mode of inhibition for α-glucosidase and butyrylcholinesterase enzymes. In addition, molecular docking studies identified crucial binding interactions of ligands with the enzyme's active site. Conclusion: These molecules may serve as a potential drug candidate to cure diabetes, Alzheimer's disease and oxidative stress in the future.


Assuntos
Doença de Alzheimer , Diabetes Mellitus , Humanos , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Simulação de Acoplamento Molecular , Inibidores da Colinesterase/química , alfa-Glucosidases/metabolismo , Piranos/uso terapêutico , Cinética , alfa-Amilases/metabolismo , Pirazóis/uso terapêutico , Relação Estrutura-Atividade , Estrutura Molecular
7.
Front Endocrinol (Lausanne) ; 13: 1022623, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36313779

RESUMO

In an attempt to find new targets for α-amylase and α-glucosidase for the treatment of type 2 diabetes mellitus, the present study aims in determining the anti-diabetic potential of synthesized dihydropyrimidinone derivatives. The in vitro α-glucosidase and α-amylase inhibitory activity was performed and the molecular docking analysis of the ligand in the active binding site of target protein was determined. The results revealed significant percent inhibition of α-glucosidase by the compound 6-benzyl-4-(4-hydroxyphenyl)-3,4,6,7-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-2,5-dione (compound A). The active compound showed 81.99% inhibition when compared to standard ascorbic acid having percent inhibition 81.18%. The IC50 of active compound (A) showed to be 1.02 µg/ml. The molecular docking analysis revealed that the ligand bound to the active binding site of protein with the lowest binding energy of -7.9 kcal/mol that was also significantly similar to standard having -7.8 kcal/mol binding energy. The molecular dynamic simulation studies also revealed stable binding of ligand in the active binding site of protein with low RMSD of 1.7 Å similar to the protein RMSD 1.6Å In conclusion, the study revealed a potential new target against α-glucosidase to treat type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2 , alfa-Glucosidases , Humanos , alfa-Glucosidases/metabolismo , Simulação de Acoplamento Molecular , Ligantes , Diabetes Mellitus Tipo 2/tratamento farmacológico , alfa-Amilases/metabolismo
8.
J Chromatogr A ; 1683: 463550, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36219969

RESUMO

Mussel-inspired catechol-amine co-deposition is an effective modification strategy for various materials. In this work, polyvinylidene fluoride (PVDF) membrane was employed as the carrier for α-glucosidase immobilization. By virtue of the co-polymerization of tannic acid (TA) and 3-aminopropyltriethoxysilane (APTES) and the hydrolysis of APTES, a hierarchical layer-colloidal nanospheres coating was decorated on the surface of PVDF membrane. Subsequently, α-glucosidase was covalently bound to the modified PVDF membrane through Schiff base reaction and Michael addition reaction between the residual quinine groups in the coating and the amino groups in enzyme molecules. Several parameters affecting the immobilization procedure were investigated thoroughly. The morphology and functional groups of the prepared composite were characterized by scanning electron microscopy (SEM), Fourier transform infrared-Attenuated total reflectance spectroscopy (FTIR-ATR), and X-ray photoelectron spectroscopy (XPS). Combined with capillary electrophoresis (CE) analysis, the performance, enzyme reaction kinetics and inhibition kinetics of PVDF-immobilized α-glucosidase were studied. The immobilized enzyme exhibited the enhanced tolerance to temperature and pH value. In addition, it possessed good reusability maintaining 77.1% of initial relative activity after 11 recycles, and batch-to-batch reproducibility with RSD of 4.3% (n = 10). The Michaelis-Menten constant (Km) of immobilized enzyme was calculated to be 4.16 mM, and IC50 value of acarbose was 0.10 µM. Finally, the PVDF-immobilized α-glucosidase was applied to screening potential inhibitors from 13 kinds of traditional Chinese medicines (TCMs), among which Sanguisorba Radix exhibited the strongest inhibitory activity. The positive results suggested that TA/APTES co-deposition was a simple and mild functionalization method for chemically inert polymer membrane and the proposed screening method was a reliable approach for discovering enzyme inhibitors from TCMs.


Assuntos
Enzimas Imobilizadas , alfa-Glucosidases , alfa-Glucosidases/metabolismo , Enzimas Imobilizadas/metabolismo , Taninos/química , Polímeros , Bases de Schiff , Acarbose , Reprodutibilidade dos Testes , Quinina , Concentração de Íons de Hidrogênio , Propilaminas , Inibidores Enzimáticos , Catecóis
9.
Molecules ; 27(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36296403

RESUMO

Diabetes mellitus is a chronic metabolic disorder in which the pancreas secretes insulin but the body cells do not recognize it. As a result, carbohydrate metabolism causes hyperglycemia, which may be fatal for various organs. This disease is increasing day by day and it is prevalent among people of all ages, including young adults and children. Acarbose and miglitol are famous alpha-glucosidase inhibitors but they complicate patients with the problems of flatulence, pain, bloating, diarrhea, and loss of appetite. To overcome these challenges, it is crucial to discover new anti-diabetic drugs with minimal side effects. For this purpose, benzotriazinone sulfonamides were synthesized and their structures were characterized by FT-IR, 1H-NMR and 13C-NMR spectroscopy. In vitro alpha-glucosidase inhibition studies of all synthesized hybrids were conducted using the spectrophotometric method. The synthesized compounds revealed moderate-to-good inhibition activity; in particular, nitro derivatives 12e and 12f were found to be the most effective inhibitors against this enzyme, with IC50 values of 32.37 ± 0.15 µM and 37.75 ± 0.11 µM. In silico studies, including molecular docking as well as DFT analysis, also strengthened the experimental findings. Both leading compounds 12e and 12f showed strong hydrogen bonding interactions within the enzyme cavity. DFT studies also reinforced the strong binding interactions of these derivatives with biological molecules due to their lowest chemical hardness values and lowest orbital energy gap values.


Assuntos
Diabetes Mellitus , Insulinas , Criança , Humanos , Inibidores de Glicosídeo Hidrolases/química , alfa-Glucosidases/metabolismo , Simulação de Acoplamento Molecular , Acarbose , Sulfonamidas/uso terapêutico , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Diabetes Mellitus/tratamento farmacológico , Sulfanilamida , Insulinas/uso terapêutico , Estrutura Molecular
10.
Molecules ; 27(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36296520

RESUMO

Diabetes mellitus is one of the most chronic metabolic diseases. In the past few years, our research group has synthesized and evaluated libraries of heterocyclic analogs against α-glucosidase and α-amylase enzymes and found encouraging results. The current study comprises the evaluation of benzimidazole-bearing thiosemicarbazone as antidiabetic agents. A library of fifteen derivatives (7-21) was synthesized, characterized via different spectroscopic techniques such as HREI-MS, NMR, and screened against α-glucosidase and α-amylase enzymes. All derivatives exhibited excellent to good biological inhibitory potentials. Derivatives 19 (IC50 = 1.30 ± 0.20 µM and 1.20 ± 0.20 µM) and 20 (IC50 = 1.60 ± 0.20 µM and 1.10 ± 0.01 µM) were found to be the most potent among the series when compared with standard drug acarbose (IC50 = 11.29 ± 0.07 and 11.12 ± 0.15 µM, respectively). These derivatives may potentially serve as the lead candidates for the development of new therapeutic representatives. The structure-activity relationship was carried out for all molecules which are mainly based upon the pattern of substituent/s on phenyl rings. Moreover, in silico docking studies were carried out to investigate the active binding mode of selected derivatives with the target enzymes.


Assuntos
Inibidores de Glicosídeo Hidrolases , Tiossemicarbazonas , Inibidores de Glicosídeo Hidrolases/química , alfa-Amilases , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Acarbose , Tiossemicarbazonas/farmacologia , Relação Estrutura-Atividade , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Benzimidazóis/química , Estrutura Molecular
11.
Molecules ; 27(20)2022 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-36296528

RESUMO

The ambident electrophilic character of the 5-bromo-2-hydroxychalcones and the binucleophilic nature of 2-aminothiophenol were exploited to construct the 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines. The structures and conformation of these 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines were established with the use of spectroscopic techniques complemented with a single crystal X-ray diffraction method. Both 1H-NMR and IR spectroscopic techniques confirmed participation of the hydroxyl group in the intramolecular hydrogen-bonding interaction with a nitrogen atom. SC-XRD confirmed the presence of a six-membered intramolecularly hydrogen-bonded pseudo-aromatic ring, which was corroborated by the DFT method on 2b as a representative example in the gas phase. Compounds 2a (Ar = -C6H5), 2c (Ar = -C6H4(4-Cl)) and 2f (Ar = -C6H4(4-CH(CH3)2) exhibited increased inhibitory activity against α-glucosidase compared to acarbose (IC50 = 7.56 ± 0.42 µM), with IC50 values of 6.70 ± 0.15 µM, 2.69 ± 0.27 µM and 6.54 ± 0.11 µM, respectively. Compound 2f, which exhibited increased activity against α-glucosidase, also exhibited a significant inhibitory effect against α-amylase (IC50 = 9.71 ± 0.50 µM). The results of some computational approaches on aspects such as noncovalent interactions, calculated binding energies for α-glucosidase and α-amylase, ADME (absorption, distribution, metabolism and excretion) and bioavailability properties, gastrointestinal absorption and blood-brain barrier permeability are also presented.


Assuntos
Tiazepinas , alfa-Glucosidases , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Acarbose/farmacologia , Simulação de Acoplamento Molecular , alfa-Amilases , Hidrogênio , Nitrogênio , Relação Estrutura-Atividade , Estrutura Molecular
12.
Molecules ; 27(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36296676

RESUMO

Cotoneaster species have gained significant importance in traditional Asian medicine for their ability to prevent and treat hyperglycemia and diabetes. Therefore, in this study, some aspects of the beneficial health effects of hydromethanolic extracts of C. bullatus, C. zabelii, and C. integerrimus leaves and fruits were evaluated, including their influence on α-glucosidase, α-amylase, and nonenzymatic protein glycation. The activity was investigated in relation to the polyphenolic profile of the extracts determined by UV-spectrophotometric and HPLC-PDA-fingerprint methods. It was revealed that all leaf and fruit extracts are a promising source of biological components (caffeic acid pseudodepsides, proanthocyanidins, and flavonols), and the leaf extracts of C. bullatus and C. zabelii contain the highest levels of polyphenols (316.3 and 337.6 mg/g in total, respectively). The leaf extracts were also the most effective inhibitors of digestive enzymes and nonenzymatic protein glycation. IC50 values of 8.6, 41.8, and 32.6 µg/mL were obtained for the most active leaf extract of C. bullatus (MBL) in the α-glucosidase, α-amylase, and glycation inhibition tests, respectively. In the kinetic study, MBL was displayed as a mixed-type inhibitor of both enzymes. The correlations between the polyphenol profiles and activity parameters (|r| > 0.72, p < 0.05) indicate a significant contribution of proanthocyanidins to the tested activity. These results support the traditional use of Cotoneaster leaves and fruits in diabetes and suggest their hydrophilic extracts be promising in functional applications.


Assuntos
Diabetes Mellitus , Proantocianidinas , Rosaceae , alfa-Amilases , alfa-Glucosidases/metabolismo , Frutas/metabolismo , Polifenóis/farmacologia , Antioxidantes/farmacologia , Extratos Vegetais/farmacologia , Rosaceae/metabolismo , Fenóis/farmacologia , Hipoglicemiantes/farmacologia , Flavonóis , Inibidores de Glicosídeo Hidrolases/farmacologia
13.
Molecules ; 27(20)2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36296720

RESUMO

A unique series of sulphonamide derivatives was attempted to be synthesized in this study using a new and effective method. All of the synthesized compounds were verified using several spectroscopic methods, including FTIR, 1H-NMR, 13C-NMR, and HREI-MS, and their binding interactions were studied using molecular docking. The enzymes urease and α-glucosidase were evaluated against each derivative (1-15). When compared to their respective standard drug such as acarbose and thiourea, almost all compounds were shown to have excellent activity. Among the screened series, analogs 5 (IC50 = 3.20 ± 0.40 and 2.10 ± 0.10 µM) and 6 (IC50 = 2.50 ± 0.40 and 5.30 ± 0.20 µM), emerged as potent molecules when compared to the standard drugs acarbose (IC50 = 8.24 ± 0.08 µM) and urease (IC50 = 7.80 ± 0.30). Moreover, an anti-microbial study also demonstrated that analogs 5 and 6 were found with minimum inhibitory concentrations (MICs) in the presence of standard drugs streptomycin and terinafine.


Assuntos
Urease , alfa-Glucosidases , alfa-Glucosidases/metabolismo , Simulação de Acoplamento Molecular , Benzeno , Hidrazinas , Derivados de Benzeno , Acarbose/farmacologia , Relação Estrutura-Atividade , Tioureia/química , Sulfanilamida , Estreptomicina , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Estrutura Molecular , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química
14.
Nutrients ; 14(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36297098

RESUMO

In folk medicine, Ficus tikoua (F. tikoua) has been used to treat diabetes for a long time, but there is a rare modern pharmacological investigation for its antidiabetic effect and mechanisms. Our study aimed to evaluate its hypoglycemic effect using in vitro and in vivo experimental models and then explore the possible mechanisms. In the ethanol extracts and fractions of F. tikoua, n-butanol fraction (NBF) exhibited the most potent effect on inhibiting α-glucosidase activity (IC50 = 0.89 ± 0.04 µg/mL) and promoting glucose uptake in 3T3-L1 adipocytes. Further animal experiments showed that NBF could play an antidiabetic role by ameliorating random blood glucose, fasting blood glucose, oral glucose tolerance, HbA1c level, and islets damage in diabetic mice. Then, the activities of the five subfractions of NBF (NBF1-NBF5) were further evaluated; NBF2 showed stronger α-glucosidase inhibition activities (IC50 = 0.32 ± 0.05 µg/mL) than NBF. Moreover, NBF2 also possessed the ability to promote glucose uptake, which was mediated via P13K/AKT and AMPK pathways. This study demonstrated that F. tikoua possesses antidiabetic efficacy in vitro and in vivo and provided a scientific basis for its folk medicinal use. NBF2 might be potential natural candidate drugs to treat diabetes mellitus. It is the first time the antidiabetic activity and the potential mechanisms of NBF2 were reported.


Assuntos
Diabetes Mellitus Experimental , Ficus , Extratos Vegetais , Animais , Camundongos , alfa-Glucosidases/metabolismo , Proteínas Quinases Ativadas por AMP , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Etanol , Ficus/química , Hemoglobina A Glicada , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt
15.
PLoS One ; 17(10): e0276984, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36301972

RESUMO

BACKGROUND AND OBJECTIVE: Annona muricata L. peel has been recognized for many ethnobotanical uses, including diabetes management. However, limited detailed scientific information about its mechanism of antidiabetic activity exists. The objective of this study was to evaluate the anti-diabetic properties of an aqueous extract of A. muricata peel (AEAMP) and its mechanism of action on alloxan-induced diabetic rats. METHODS: In vitro antidiabetic assays, such as α-amylase and α-glucosidase were analyzed on AEAMP. Alloxan monohydrate (150 mg/kg b.w) was used to induce diabetes in the rats. 150 mg/kg b.w positive control group doses of 6.67, 13.53, and 27.06 mg/kg were administered to 3 groups for twenty-one days. The positive control group was administered 30 mg/kg of metformin. The negative and normal control groups were administered distilled water. The fasting blood glucose, serum insulin, lipid profile, inflammatory cytokines, antioxidant markers, carbohydrate metabolizing enzymes, and liver glycogen were analyzed as well as PI3K/AKT and apoptotic markers PCNA and Bcl2 by RT-PCR. RESULTS: AEAMP inhibited α-amylase and α-glucosidase enzymes more effectively than acarbose. AEAMP reduced FBG levels, HOMA-IR, G6P, F-1,6-BP, MDA, TG, TC, AI, CRI, IL-6, TNF-α, and NF-κB in diabetic rats. Furthermore, in diabetic rats, AEAMP improved serum insulin levels, HOMA-ß, hexokinase, CAT, GST, and HDL-c. Liver PI3K, liver PCNA and pancreas PCNA were not significantly different in untreated diabetic rats when compared to normal rats suggesting alloxan induction of diabetes did not downregulate the mRNA expression of these genes. AEAMP significantly up-regulated expression of AKT and Bcl2 in the liver and pancreatic tissue. It is interesting that luteolin and resorcinol were among the constituents of AEAMP. CONCLUSIONS: AEAMP can improve ß-cell dysfunction by upregulating liver AKT and pancreatic PI3K and AKT genes, inhibiting carbohydrate metabolizing enzymes and preventing apoptosis by upregulating liver and pancreatic Bcl2. However, the potential limitation of this study is the unavailability of equipment and techniques for collecting more data for the study.


Assuntos
Annona , Diabetes Mellitus Experimental , Hipoglicemiantes , Extratos Vegetais , Animais , Ratos , Aloxano/farmacologia , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo , Annona/química , Apoptose , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/uso terapêutico , Inflamação/tratamento farmacológico , Insulinas/sangue , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/uso terapêutico , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação para Cima
16.
Molecules ; 27(19)2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36234994

RESUMO

In this study, hybrid analogs of benzimidazole containing a thiazole moiety (1-17) were afforded and then tested for their ability to inhibit α-amylase and α-glucosidase when compared to acarbose as a standard drug. The recently available analogs showed a wide variety of inhibitory potentials that ranged between 1.31 ± 0.05 and 38.60 ± 0.70 µM (against α-amylase) and between 2.71 ± 0.10 and 42.31 ± 0.70 µM (against α-glucosidase) under the positive control of acarbose (IC50 = 10.30 ± 0.20 µM against α-amylase) (IC50 = 9.80 ± 0.20 µM against α-glucosidase). A structure-activity relationship (SAR) study was carried out for all analogs based on substitution patterns around both rings B and C respectively. It was concluded from the SAR study that analogs bearing either substituent(s) of smaller size (-F and Cl) or substituent(s) capable of forming hydrogen bonding (-OH) with the catalytic residues of targeted enzymes enhanced the inhibitory potentials. Therefore, analogs 2 (bearing meta-fluoro substitution), 3 (having para-fluoro substitution) and 4 (with ortho-fluoro group) showed enhanced potency when evaluated against standard acarbose drug with IC50 values of 4.10 ± 0.10, 1.30 ± 0.05 and 1.90 ± 0.10 (against α-amylase) and 5.60 ± 0.10, 2.70 ± 0.10 and 2.90 ± 0.10 µM (against α-glucosidase), correspondingly. On the other hand, analogs bearing substituent(s) of either a bulky nature (-Br) or that are incapable of forming hydrogen bonds (-CH3) were found to lower the inhibitory potentials. In order to investigate the binding sites for synthetic analogs and how they interact with the active areas of both targeted enzymes, molecular docking studies were also conducted on the potent analogs. The results showed that these analogs adopted many important interactions with the active areas of enzymes. The precise structure of the newly synthesized compounds was confirmed using several spectroscopic techniques as NMR and HREI-MS.


Assuntos
alfa-Amilases , alfa-Glucosidases , Acarbose/farmacologia , Benzimidazóis/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química , alfa-Glucosidases/metabolismo
17.
Molecules ; 27(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36235098

RESUMO

Amylase and glucosidase enzymes are the primary harmful source in the development of the chronic condition known as diabetes mellitus. The main function of these enzymes is to break the macromolecules into simple sugar units which are directly involved in the solubility of blood, hence increasing blood glucose levels. To overcome this effect, there is a need for a potent and effective inhibitor that inhibits the conversion of macromolecules of sugar into its smaller units. In this regard, we synthesized thiazolidinone-based indole derivatives (1-20). The synthesized derivatives were evaluated for α-amylase and α-glucosidase inhibitory activity. Different substituted derivatives were found with moderate to good potentials having IC50 values ranging, for α-amylase, from 1.50 ± 0.05 to 29.60 ± 0.40 µM and, for α-glucosidase, from IC50 = 2.40 ± 0.10 to 31.50 ± 0.50 µM. Among the varied substituted compounds, the most active analogs four (1.80 ± 0.70 and 2.70 ± 0.70), five (1.50 ± 0.05 and 2.40 ± 0.10, respectively) of the series showed few folds better inhibitory activity than standard drug acarbose (IC50 = 10.20 ± 0.10 and 11.70 ± 0.10 µM, respectively). Moreover, structure-activity relationship (SAR) was established and binding interactions were analyzed for ligands and proteins (α-amylase and α-glucosidase) through a molecular docking study.&nbsp.


Assuntos
Glucosidases , alfa-Glucosidases , Acarbose , Amilases/metabolismo , Glicemia , Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Indóis/química , Indóis/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptores de Droga , Relação Estrutura-Atividade , alfa-Amilases , alfa-Glucosidases/metabolismo
18.
Molecules ; 27(19)2022 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-36235251

RESUMO

Diabetes mellitus (DM) is a global health concern that is associated with several micro- and macrovascular complications. We evaluated several important medicinal plant constituents, including polyphenols and flavonoids, for α-glucosidase inhibition, AGEs' inhibitory activities using oxidative and no-oxidative assays, the inhibition of protein cross link formation, 15-lipoxydenase inhibition and molecular docking. The molecular docking studies showed high binding energies of flavonoids for transcriptional regulars 1IK3, 3TOP and 4F5S. In the α-glucosidase inhibition assay, a significant inhibition was noted for quercitrin (IC50 7.6 µg/mL) and gallic acid (IC50 8.2 µg/mL). In the AGEs inhibition assays, quercetin showed significant results in both non-oxidative and (IC50 0.04 mg/mL) and oxidative assays (IC50 0.051 mg/mL). Furthermore, quercitrin showed inhibitory activity in the non-oxidative (IC50 0.05 mg/mL) and oxidative assays (IC50 0.34 mg/mL). A significant inhibition of protein cross link formation was observed by SDS-PAGE analysis. Quercitrin (65%) and quercetin (62%) showed significant inhibition of 15-lipoxygenase. It was thus concluded that flavonoids and other polyphenols present in plant extracts can be effective in management of diabetes and allied co-morbidities.


Assuntos
Diabetes Mellitus , Hipoglicemiantes , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Araquidonato 15-Lipoxigenase , Flavonoides/farmacologia , Ácido Gálico/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Quercetina/farmacologia , alfa-Glucosidases/metabolismo
19.
Molecules ; 27(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36144478

RESUMO

Diabetes is a chronic metabolic disease, whereas α-glucosidases are key enzymes involved in the metabolism of starch and glycogen. There is a long history of the use of mulberry leaf (the leaf of Morus alba) as an antidiabetic herb in China, and we found that chalcomoracin, one of the specific Diels-Alder adducts in mulberry leaf, had prominent α-glucosidase inhibitory activity and has the potential to be a substitute for current hypoglycemic drugs such as acarbose, which have severe gastrointestinal side effects. In this study, chalcomoracin was effectively isolated from mulberry leaves, and its α-glucosidase inhibition was studied via enzymatic kinetics, isothermal titration (ITC) and molecular docking. The results showed that chalcomoracin inhibited α-glucosidase through both competitive and non-competitive manners, and its inhibitory activity was stronger than that of 1-doxymycin (1-DNJ) but slightly weaker than that of acarbose. ITC analysis revealed that the combination of chalcomoracin and α-glucosidase was an entropy-driven spontaneous reaction, and the molecular docking results also verified this conclusion. During the binding process, chalcomoracin went into the "pocket" of α-glucosidase via hydrophobic interactions, and it is linked with residues Val544, Asp95, Ala93, Gly119, Arg275 and Pro287 by hydrogen bonds. This study provided a potential compound for the prevention and treatment of diabetes and a theoretical basis for the discovery of novel candidates for α-glycosidase inhibitors.


Assuntos
Diabetes Mellitus , Morus , Acarbose/análise , Acarbose/farmacologia , Benzofuranos , Glicogênio/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hipoglicemiantes/metabolismo , Simulação de Acoplamento Molecular , Morus/química , Folhas de Planta/química , Amido/metabolismo , alfa-Glucosidases/metabolismo
20.
Molecules ; 27(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36144750

RESUMO

The α-glucosidase enzyme, located in the brush border of the small intestine, is responsible for overall glycemic control in the body. It hydrolyses the 1,4-linkage in the carbohydrates to form blood-absorbable monosaccharides that ultimately increase the blood glucose level. α-Glucosidase inhibitors (AGIs) can reduce hydrolytic activity and help to control type 2 diabetes. Aiming to achieve this, a novel series of 1-benzyl-3-((2-substitutedphenyl)amino)-2-oxoethyl)-2-(morpholinomethyl)-1H-benzimidazol-3-ium chloride was synthesized and screened for its α-glucosidase inhibitory potential. Compounds 5d, 5f, 5g, 5h and 5k exhibited better α-glucosidase inhibitions compared to the standard drug (acarbose IC50 = 58.8 ± 0.012 µM) with IC50 values of 15 ± 0.030, 19 ± 0.060, 25 ± 0.106, 21 ± 0.07 and 26 ± 0.035 µM, respectively. Furthermore, the molecular docking studies explored the mechanism of enzyme inhibitions by different 1,2,3-trisubstituted benzimidazolium salts via significant ligand-receptor interactions.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores de Glicosídeo Hidrolases , Acarbose , Glicemia , Cloretos , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfolinas , Sais/farmacologia , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
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