Indole-3-acetamides: As Potential Antihyperglycemic and Antioxidant Agents; Synthesis, In Vitro α-Amylase Inhibitory Activity, Structure-Activity Relationship, and In Silico Studies.
Ontology highlight
ABSTRACT:
SUBMITTER: Kanwal
PROVIDER: S-EPMC7841949 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The Michael addition reaction of barbituric acid with chalcones incorporating the indole scaffold was achieved by using a highly efficient bimetallic Iron-palladium catalyst in the presence of acetylacetone (acac). This catalytic approach produced the desired products in a simple operation and low catalyst loading with acceptable yield of the new hybrids. All tested compounds were subjected for biological activity on ?-glucosidase and ?-amylase. The results revealed that all synthesized compounds exhibited very good activity against both enzymes when compared to positive control (acarbose). Moreover, compound 5o showed the best activity whereas its IC50 (?M) are 13.02+0.01 and 21.71+0.82 for ?-glucosidase and ?-amylase respectively. Both compounds 5o and 5l exhibited high similarity in binding mode and pose with amylase protein (4UAC). The obtained data may be used for developing potential hypoglycemic agents.
| S-EPMC6804419 | biostudies-literature
Project description:Diabetes mellitus is a major health problem globally. The management of carbohydrate digestion provides an alternative treatment. Flavonoids constitute the largest group of polyphenolic compounds, produced by plants widely consumed as food and/or used for therapeutic purposes. As such, isoxazoles have attracted the attention of medicinal chemists by dint of their considerable bioactivity. Thus, the main goal of this work was to discover new hybrid molecules with properties of both flavonoids and isoxazoles in order to control carbohydrate digestion. Moreover, the trifluoromethyl group is a key entity in drug development, due to its strong lipophilicity and metabolic stability. Therefore, the present work describes the condensation of a previously synthesized trifluoromethylated flavonol with different aryl nitrile oxides, affording 13 hybrid molecules indicated as trifluoromethylated flavonoid-based isoxazoles. The structures of the obtained compounds were deduced from by 1H NMR, 13C NMR, and HRMS analysis. The 15 newly synthesized compounds inhibited the activity of α-amylase with an efficacy ranging from 64.5 ± 0.7% to 94.7 ± 1.2% at a concentration of 50 μM, and with IC50 values of 12.6 ± 0.2 μM-27.6 ± 1.1 μM. The most effective compounds in terms of efficacy and potency were 3b, 3h, 3j, and 3m. Among the new trifluoromethylated flavonoid-based isoxazoles, the compound 3b was the most effective inhibitor of α-amylase activity (PI = 94.7 ± 1.2% at 50 μM), with a potency (IC50 = 12.6 ± 0.2 μM) similar to that of the positive control acarbose (IC50 = 12.4 ± 0.1 μM). The study of the structure-activity relationship based on the molecular docking analysis showed a low binding energy, a correct mode of interaction in the active pocket of the target enzyme, and an ability to interact with the key residues of glycosidic cleavage (GLU-230 and ASP-206), explaining the inhibitory effects of α-amylase established by several derivatives.
| S-EPMC8434401 | biostudies-literature
Project description:Diabetes has emerged as one of the largest global epidemics; it is estimated that by 2035, there will be 592 million diabetic people in the world. Brazilian biodiversity and the knowledge of traditional peoples have contributed to the treatment of several diseases, including diabetes. Apis mellifera bee tea is used by indigenous Brazilians to treat diabetes, and this traditional knowledge needs to be recorded and studied.The objective of this study was to record the use and to evaluate the antioxidant, antihyperglycemic, and antidiabetic activity of Apis mellifera bee tea, which is used by the Guarani and Kaiowá indigenous people for the treatment of diabetes. Semi-structured interviews were performed with Guarani and Kaiowá ethnic indigenous people from the State of Mato Grosso do Sul, Brazil, seeking to identify the animal species used for medicinal purposes. For the experimental procedures, tea prepared with macerated Apis mellifera bees was used. In vitro assays were performed to evaluate antioxidant activity; direct free radical scavenging, protection against oxidative hemolysis, lipid peroxidation were evaluated in human erythrocytes and potential in inhibiting the formation of advanced glycation end products (AGEs). In vivo, normoglycemic Swiss male mice treated with Apis mellifera tea (AmT) were subjected to the oral glucose tolerance test and compared with control and metformin-treated groups. Diet-induced diabetic mice were treated for 21 days with AmT and evaluated for glycemia and malondialdehyde levels in the blood, liver, nervous system, and eyes. During interviews, the indigenous people described the use of Apis mellifera bee tea for the treatment of diabetes. In in vitro assays, AmT showed direct antioxidant activity and reduced oxidative hemolysis and malondialdehyde generation in human erythrocytes. The AmT inhibited the formation of AGEs by albumin-fructose pathways and methylglyoxal products. In vivo, after oral glucose overload, normoglycemic mice treated with AmT had reduced hyperglycemia at all times evaluated up to 180 min. AmT also reduced hyperglycemia and malondialdehyde levels in the blood, liver, nervous system, and eyes of diabetic mice to similar levels as those in metformin-treated mice and normoglycemic controls. In summary, Apis mellifera bee tea showed antioxidant, antihyperglycemic, and antidiabetic activity, which provides support for the therapeutic application of Guarani and Kaiowá indigenous knowledge.
| S-EPMC5988306 | biostudies-literature
Project description:Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are rising and prey upon patients with structural lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. All mycobacterial infections require lengthy treatment regimens with undesirable side effects. Therefore, new antimycobacterial compounds with novel mechanisms of action are urgently needed. Published indole-2-carboxamides (IC) with suggested inhibition of the essential transporter MmpL3 showed good potency against whole-cell M.tb, yet had poor aqueous solubility. This project focused on retaining the required MmpL3 inhibitory pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole, mandelic acid, imidazole, and acetamide functional groups coupled to lipophilic head groups, where lead acetamide-based compounds maintained high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs, were non-cytotoxic, and were determined to be MmpL3 inhibitors.
| S-EPMC10010622 | biostudies-literature
Project description:In this study, daphnetin 1 was chosen as the lead compound, and C-3 or C-4-substituted daphnetins were designed and synthesized to explore the potential relationship between the antioxidant activities and the chemical structures of daphnetin derivatives. The antioxidant activities of the generated compounds were evaluated utilizing the free radical scavenging effect on 2,2'-diphenyl-1-picrylhydrazyl, 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonate) cation, and the ferric reducing power assays, and were then compared with those of the standard antioxidant Trolox. The results showed that the catechol group was the key pharmacophore for the antioxidant activity of the daphnetins. The introduction of an electron-withdrawing hydrophilic group at the C-4 position of daphnetin enhanced the antioxidative capacity, but this trend was not observed for C-3 substitution. In addition, introduction of a a hydrophobic phenyl group exerted negative effects on the antioxidant activity in both the C-3 and C-4 substitutions. Among all of the derivatives tested, the most powerful antioxidant was 4-carboxymethyl daphnetin (compound 9), for which the strongest antioxidant activity was observed in all of the assays. In addition, compound 9 also displayed strong pharmaceutical properties in the form of metabolic stability. To summarize, compound 9 holds great potential to be developed as an antioxidant agent with excellent antioxidant activity and proper pharmacokinetic behavior.
| S-EPMC6222747 | biostudies-literature
Project description:BACKGROUND:Momordica charantia Linn. (Cucurbitaceae), the wild variety of bitter melon and Morinda lucida Benth (Rubiaceae) were commonly used as a popular folk medicine in Benin. This research focused to measure the antioxidant and enzyme inhibitory effects of M. charantia and M. lucida leaves and their antidiabetic activity. METHODS:Antioxidant activities were evaluated by micro-dilution technique using DPPH free radical scavenging activity and ?-carotene-linoleate bleaching assay. The ?-amylase inhibition assay was carried out utilizing the 3,5-dinitrosalicylic acid procedure, while ?-glucosidase inhibition assay was demonstrated using as substrate p-nitrophenyl-?-D-glucopyranoside (PNPG). HPLC-DAD analysis was realized using a high-performance liquid chromatography systems with diode-array detector, L-3000. RESULTS:Chlorogenic acid, epicatechin, daidzein, rutin, naringin, quercetin, naringenin and genistein were identified as polyphenol compounds in the both plants extract. Dichloromethane and ethyl acetate extracts showed a good ?-amylase inhibitory activity (56.46 ± 1.96% and 58.76 ± 2.74% respectively). M. lucida methanolic extract has shown IC50 of 0.51 ± 0.01 mg/mL, which is the lowest for DPPH scavenging activity. M. lucida dichloromethane extract showed the highest inhibitory capacity of ?-glucosidase activity (82.11. ± 2.15%). CONCLUSION:These results justify some traditional medicinal uses of both plants. The purified fractions could be used in future formulations, possibly incorporated in functional foods to combat certain diseases.
| S-EPMC7230926 | biostudies-literature
Project description:ObjectiveDiabetic individuals have a higher probability of suffering from illness and death due to small blood vessel-related problems such as retinopathy, neuropathy, nephropathy, and stroke than other complications. There are many synthetic anti-diabetic agents available, but these can be expensive and have undesirable pathological effects. The enzyme α-amylase (hydrolase), catalyzes the hydrolysis of starch to maltose and glucose via the cleavage of α-1,4-glucosidic linkages. Diabetes mellitus patients may benefit from a therapeutic strategy that involves slowing the hydrolysis of starch by inhibiting the activity of α-amylase. Thus, looking for cost-effective, natural, and safe antidiabetic agents is essential. This study aims to screen phytoconstituents and evaluate the in-vitro and in-silico α-amylase inhibitory activity of the ethanolic extract of Adhatoda vasica leaves.MethodsThe extraction of Adhatoda vasica leaves was performed using ethanol via the Soxhlet extraction process. Different concentrations (100 μg/mL to 1000 μg/mL) of ethanolic extract, Acarbose, and Sitagliptin, were prepared and evaluated for α-amylase inhibitory activity using the spectrophotometric method. Molecular docking (AutodockVina 1.2.0) and toxicity profiling (SToPToX web server) studies were performed.ResultsThe ethanolic extract of Adhatoda vasica leaves showed the highest percentage inhibition against α-amylase (56.763 ± 0.0035) at a concentration of 1000 μg/mL. The in-silico study supported this inhibitory activity. Vasicoline (C5) and Quercetin (C9), the active constitute of Adhatoda vasica, showed the best binding energies of -8.3 and -8.0 Kcal/mol, respectively against α-amylase enzyme (PDBID: 4W93). A toxicity study revealed the safety profile of the plant extract.ConclusionIt was concluded that Adhatoda vasica leaves possess some bioactive compounds that are responsible for controlling blood glucose levels, and their identification, purification, and isolation may lead to the development of new therapeutic agents with fewer side effects than the available drugs.
| S-EPMC11365037 | biostudies-literature
Project description:BackgroundIndian medicinal plants used in the Ayurvedic traditional system to treat diabetes are a valuable source of novel anti-diabetic agents. Pancreatic α-amylase inhibitors offer an effective strategy to lower the levels of post-prandial hyperglycemia via control of starch breakdown. In this study, seventeen Indian medicinal plants with known hypoglycemic properties were subjected to sequential solvent extraction and tested for α-amylase inhibition, in order to assess and evaluate their inhibitory potential on PPA (porcine pancreatic α-amylase). Preliminary phytochemical analysis of the lead extracts was performed in order to determine the probable constituents.MethodsAnalysis of the 126 extracts, obtained from 17 plants (Aloe vera (L.) Burm.f., Adansonia digitata L., Allium sativum L., Casia fistula L., Catharanthus roseus (L.) G. Don., Cinnamomum verum Persl., Coccinia grandis (L.) Voigt., Linum usitatisumum L., Mangifera indica L., Morus alba L., Nerium oleander L., Ocimum tenuiflorum L., Piper nigrum L., Terminalia chebula Retz., Tinospora cordifolia (Willd.) Miers., Trigonella foenum-graceum L., Zingiber officinale Rosc.) for PPA inhibition was initially performed qualitatively by starch-iodine colour assay. The lead extracts were further quantified with respect to PPA inhibition using the chromogenic DNSA (3, 5-dinitrosalicylic acid) method. Phytochemical constituents of the extracts exhibiting≥ 50% inhibition were analysed qualitatively as well as by GC-MS (Gas chromatography-Mass spectrometry).ResultsOf the 126 extracts obtained from 17 plants, 17 extracts exhibited PPA inhibitory potential to varying degrees (10%-60.5%) while 4 extracts showed low inhibition (< 10%). However, strong porcine pancreatic amylase inhibitory activity (> 50%) was obtained with 3 isopropanol extracts. All these 3 extracts exhibited concentration dependent inhibition with IC50 values, viz., seeds of Linum usitatisumum (540 μgml-1), leaves of Morus alba (1440 μgml-1) and Ocimum tenuiflorum (8.9 μgml-1). Acarbose as the standard inhibitor exhibited an IC50 (half maximal inhibitory concentration)value of 10.2 μgml-1. Phytochemical analysis revealed the presence of alkaloids, tannins, cardiac glycosides, flavonoids, saponins and steroids with the major phytoconstituents being identified by GC-MS.ConclusionsThis study endorses the use of these plants for further studies to determine their potential for type 2 diabetes management. Results suggests that extracts of Linum usitatisumum, Morus alba and Ocimum tenuiflorum act effectively as PPA inhibitors leading to a reduction in starch hydrolysis and hence eventually to lowered glucose levels.
| S-EPMC3037352 | biostudies-literature
Project description:The aim of this study was to compare the phenolic compound profiles and antioxidant capacities of eight varieties of longan (Dimocarpus longan Lour.) planted in the middle and upper Yangtze River area. The total polyphenols content (TPC) and total flavonoids content (TFC) of dried longan pulp ranged from 1.07?±?0.05 to 1.22?±?0.05 mg gallic acid equivalents/g and 0.25?±?0.07 to 0.87?±?0.14 mg rutin equivalents/g. UHPLC-QqQ-MS/MS analysis revealed 12 individual polyphenol compounds in longan. The Fuwan8, Dongliang and FD97 varieties showed the strongest DPPH scavenging activity (IC50 of 1.03 g/mL). The highest ABTS+ scavenging activity was found in the Dongliang. In the enzyme assays, the Fuwan8 and Dongliang varieties demonstrated maximum ?-amylase and ?-glucosidase inhibition activities, with values of 97.56 and 88.58%, respectively. The principal component analysis indicated that the Rongyu8 and Songfengben cultivars have nearly analogous polyphenol compounds.
| S-EPMC7221113 | biostudies-literature
Project description:Reducing carbohydrates digestion by having a low glycaemic index (GI) foods has been linked to weight loss. Inhibiting related enzymes is an alternative way to decrease carbohydrate digestion. RCM-107 (Slimming Plus), an eight-herb formula that is modified from RCM-104, indicated significant weight-loss action in clinical trials. However, no published research has studied its mechanism of action on reducing carbohydrate absorption via suppressing the activities of porcine pancreatic alpha-amylase (PPA). In this paper, we used fluorescence PPA inhibition assay to investigate the inhibitory effects of RCM-107 and the individual herbs present in this herbal mixture on amylase activity. Subsequently, molecular docking predicted the key active compounds that may be responsible for the enzyme inhibition. According to our results, both the RCM-107 formula and several individual herbs displayed α-amylase inhibitory effects. Also, marginal synergistic effects of RCM-107 were detected. In addition, alisol B, (-)-epigallocatechin-3-gallate (EGCG) and plantagoside have been predicted as the key active compounds that may be responsible for the α-amylase inhibition effect of RCM-107 according to inter-residue contact analysis. Finally, Glu233, Gln63, His305, Asp300 and Tyr151 are predicted to be markers of important areas with which potential amylase inhibitors would interact. Therefore, our data has provided new knowledge on the mechanisms of action of the RCM-107 formula and its individual herbal ingredients for weight loss, in terms of decreasing carbohydrate digestion via the inhibition of pancreatic alpha-amylase.
| S-EPMC7190128 | biostudies-literature