Pancreatic Α-amylase Research Articles

Inhibition of Human Salivary and Pancreatic α-Amylase by Resveratrol Oligomers.

A key strategy to mitigate postprandial hyperglycemia involves inhibiting α-amylases, which commence the starch digestion process in the gut. This study examined the inhibitory effects of resveratrol and stilbenoid tetramers, vaticanol B, (-)-hopeaphenol, and vatalbinoside A on human salivary and pancreatic α-amylases experimentally and through molecular docking studies. Vaticanol B demonstrated the most potent inhibition with IC50 values of 5.3 ± 0.3 μM for salivary and 6.1 ± 0.5 μM for pancreatic α-amylase (compared to acarbose with IC50 values of 1.2 ± 0.1 μM and 0.5 ± 0.0 μM, respectively). Kinetic analysis suggested a competitive inhibition mode for vaticanol B. Resveratrol and vatalbinoside A were poor inhibitors of human α-amylases, while (-)-hopeaphenol exhibited moderate inhibition. Molecular docking supported the inhibition data, and several aspects of the structural configurations explained the stronger inhibition exerted by vaticanol B. Overall, vaticanol B shows promise as a natural alternative to acarbose for inhibiting α-amylase.

A promising α-amylase inhibitor based on the 2-(2-hydrazinyl) thiazole scaffolds: synthesis, docking studies and biological evaluation

A series of novel hydrazinyl-based thiazole scaffolds were designed, synthesized, and evaluated for their anti-diabetic activity. The cyclocondensation reaction of the appropriately substituted acetophenones 1, thiosemicarbazide 2, and appropriate phenacyl bromide 3 allowed for the creation of a new series of hydrazinyl-based thiazole scaffolds (4a–h). The newly generated compounds were characterized using mass spectrometry,1H NMR, IR, and 13C NMR techniques. The novel hydrazinyl-based thiazole scaffolds were evaluated by the in vitro α-amylase inhibitory assay. Hydrazinyl-based thiazole scaffolds 4a, 4b, 4d, and 4f showed good activity compared to acarbose as a standard reference. Although insulin is a necessary medication for the treatment of diabetes, it carries a significant risk. We believe that thiazole scaffolds based on hydrazinyl structural motive provide recommendations for designing and producing novel anti-diabetic drugs, which are critically needed. Moreover, these compounds show a strong affinity for the pancreatic α-amylase protein binding site, suggesting greater inhibitory capability at the cellular level, and molecular docking studies have demonstrated their better-fit potential as anti-diabetic agents. This indicates the versatility of the hydrazinyl-based thiazole molecules to achieve new classes of anti-diabetic scaffold.

Quinoline Based thiazolidinediones: Design, Synthesis, In Silico, In Vitro, Antioxidant and Antidiabetic Evaluation

AbstractIn the present research work a sequence of substituted quinoline based thiazolidinedione moieties (12a–h) were designed and synthesized as potential antidiabetic agents. Pancreatic α‐amylase (PAA) and intestinal α‐glucosidase (IAG) enzymes were considered as potential targets for effective treatment of diabetes. The potential of all compounds (12a–h) was assessed in vitro against PAA and IAG using acarbose as standard. The results suggested that compound 12h has shown superior PAA and IAG inhibitory activity with respective to standard (IC50 = 4.683 ± 0.06 µM and 2.456 ± 0.07 µM). Furthermore, using computational (in silico) studies like AutoDock and Desmond, predicted the significant binding interactions responsible for the activity of all compounds (12a–h) at the active site of enzymes, while SwissADME and Osiris property explorer tools computed in silico drug likeliness and toxicity properties. The RMSD, RMSF, Rg and protein ligand contacts, confirmed the stable binding of compound 12h and 12g with the both PAA and IAG proteins. The in silico results confirmed the 12h molecule as a superior drug with high binding affinity and good drug likeness against PAA and IAG, confirming in vitro results. We also studied antioxidant activity (AOA) of all synthesized compounds and results confined that the compound 12h has good antioxidant potential (IC50 = 5.04 ± 0.054 µM) among all other compounds. In conclusion, in vitro, in silico and antioxidant studies revealed 12h compound was found to be potential compound.

Hypoglycemic Properties of Leccinum scabrum Extracts-An In Vitro Study on α-Glucosidase and α-Amylase Inhibition and Metabolic Profile Determination.

Type-2 diabetes affects an increasing percentage of the world's population and its control through dietary management, involving the consumption of health-promoting foods or their derived supplements, is a common strategy. Several mushroom species have been demonstrated to be endowed with antidiabetic properties, resulting from their ability in improving insulin sensitivity and production, or inhibiting the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase. This study aimed to investigate for the first time the hypoglycemic properties of the edible mushroom Leccinum scabrum (Bull.) Gray. Mushroom extracts were prepared through the microwave-assisted extraction (MAE) technique using green solvents with different polarity degrees. The inhibition activity of all the obtained extracts on both α-glucosidase and α-amylase was evaluated and the highest activity was observed for the EtOAc extract which showed an IC50 value about 60-fold lower than the reference compound 1-deoxynojirimycin (DNJ) on α-glucosidase (0.42 ± 0.02 and 25.4 ± 0.6 µg/mL, respectively). As expected on the basis of the literature data concerning both α-glucosidase and α-amylase inhibition, a milder inhibition activity on pancreatic α-amylase was observed. Preliminary in vivo tests on Drosophila melanogaster carried out on the most active obtained extract (EtOAc) confirmed the in vitro observed hypoglycemic activity. Finally, the EtOAc extract metabolic profile was determined through GC-MS and HRMS analyses.

Sustainable management of rosemary wastewater and essential oil in agri-environmental bioprocessing

In agriculture, fragrant and medicinal plants offer significant untapped potential for generating biomass-derived materials, particularly from wastewater by-products. In this context, the present study investigates the chemical compositions, antioxidant capacities, antimicrobial properties, acute oral toxicity, and diabetes management potential of wastewater by-products and essential oil from R. tournefortii de Noé. Utilizing advanced analytical techniques, including ATR-FTIR, GC/MS, and HPLC-DAD, were employed to conduct the analyses. ATR-FTIR analysis revealed intricate molecular compositions in both the essential oil and wastewater, confirming terpenoids, phenolic acids, and other functional groups. GC/MS and HPLC-DAD identified dominant compounds in the essential oil, notably camphor (25.49%) and 1,8-cineole (18.03%), while the wastewater contained significant levels of hydroxycinnamic acids such as caffeic acid (23.51%) and rosmarinic acid (21.15%). In terms of bioactivity, the essential oil demonstrated robust antimicrobial effects, with inhibition zones up to 17.1 mm, whereas the wastewater exhibited moderate activity, with zones up to 15.15 mm. Additionally, antioxidant assessments revealed exceptional potency of the wastewater, with IC50 values of 0.046 ± 0.007 mg/mL for DPPH, 0.082 ± 0.013 mg/mL for ABTS, and 2.45 ± 0.71 mg/mL for the beta-carotene/linoleate model system, surpassing the essential oil. Furthermore, both the essential oil and wastewater showed significant inhibitory effects on pancreatic α-amylase, crucial for diabetes management, with wastewater demonstrating remarkable inhibition (IC50 = 0.48 ± 0.021 mg/mL). Acute oral toxicity assessment confirmed the safety of these components, alleviating concerns about potential adverse effects. In summary, these findings highlight the untapped potential and environmental significance of wastewater by-products as valuable resources, positioning R. tournefortii de Noé's essential oil and wastewater as promising agents for sustainable healthcare and environmental sustainability.

Validated HPTLC Method for Detection of Kaempferol in <i>Moringa oleifera</i> Leaf Extract and Investigation of its Antidiabetic Potential by <i>In Vitro</i> and <i>In Silico</i> Studies

Background: Exploring traditional treatments offers valuable foundations for the innovation of new pharmaceuticals for the management of diabetes mellitus and its complications. Validation of plant extract by suitable chromatographic techniques is a part of standardization procedures. Moringa oleifera is one such traditionally used plant to be explored. Aim: The study explores the antidiabetic potential of M. oleifera through both in vitro and in silico explorations along with HPTLC method development and validation for estimation of kaempferol in M. oleifera extract. Method: Plant extract was prepared by maceration method using ethanol: water (70:25) and followed by Soxhlet(95% ethanol). Pharmacognostical analysis was conducted. In silico and in vitro antidiabetic and antioxidant studies were conducted, as well as quality control analysis was done using HPTLC method the mobile phase used was toluene: ethyl acetate: formic acid: methanol: (6:3:0.3:1v/v/v/v). Results: HPTLC analysis showed the presence of kaempferol, and the method was validated as per ICH guidelines. According to reports on molecular docking studies, several phytocompounds inhibited when porcine pancreatic α-amylase (PPA) complexed with a carbohydrate inhibitor (PDB ID: 4W93).The hydroalcoholic extract was discovered to have the ability to inhibit α-amylase, with IC50 values of 57.38588±1.92 μg/mL and 32.51564±1.59 μg/mL for standard acarbose, respectively. Conclusion: Overall, this research provides comprehensive data for the estimation of kaempferol in Moringa oleifera by HPTLC and presents valuable evidence on its antidiabetic potential both in vitro and in silico.

Inhibition of starch hydrolysis during in vitro co-digestion of pasta with phenolic compound-rich vegetable foods

The ability of phenolic compounds to inhibit amylolytic enzymes activities has been investigated, suggesting their possible role in type-2 diabetes management. However, these studies have been carried out with purified enzymes and synthetic substrates and are distant from simulating a real physiological situation. The objective of the present research was to evaluate the ability of phenolic-rich vegetable foods to inhibit starch hydrolysis during in vitro co-digestion with pasta resulting in a potential anti-diabetic effect and mimicking as closely as possible a real scenario. Some tested vegetable foods, such as capers, red-skinned onion, red radish, and olives, determined a decrease in starch hydrolysis by 21.5%–31.7% during in vitro co-digestion with pasta. The quali-quantitative phenolic profiles of in vitro co-digested samples were elucidated and selected standard compounds were tested for their ability to inhibit porcine pancreatic α-amylase and mammalian α-glucosidase. The inhibitory potential of these compounds, especially against α-glucosidase, explained the effect observed during co-digestion experiments. The most active phenolic compounds against α-glucosidase were quercetin-4’-O-glucoside, quercetin-3-O-rutinoside, luteolin-7-O-glucoside and quercetin-3-O-glucoside-4’-O-glucoside with IC50 values of 20.67, 52.23, 68.84 and 87.58 μmol/L, respectively. This is the first report suggesting that these compounds are potent inhibitors of mammalian α-glucosidase. This study indicates that consuming starchy foods (i.e., pasta) with phenolic-rich vegetable foods may result in an inhibition of starch digestion possibly reducing the post-prandial glucose levels.

Design and synthesis of new coumarin-1,2,3-triazole hybrids as new antidiabetic agents: In vitro α-amylase, α-glucosidase inhibition, anti-inflammatory, and docking study

The current study focuses on the synthesis of coumarin-triazole hybrids (7i-t) starting from 4-hydroxy benzaldehyde or 4-hydroxyacetophenone (1a-b) and propargyl bromide. On the other hand, coumarin derivatives (5c-h) were prepared by Pechmann cyclization and treated with sodium azide to give the corresponding 3-azido methyl coumarins (6c-h). Finally, 1,3-dipolar cycloaddition between compounds 6c-h and terminal alkyne 2a-b produces coumarin-triazole hybrids (7i-t) utilizing click chemistry approaches that are high yielding, wide in scope and simple to perform. The structural proofs of the newly synthesized coumarin-triazole hybrids (7i-t) are proved by various spectroscopic techniques, including IR, 1H NMR, 13C NMR, and LC-MS. The synthesized new coumarin triazole hybrids (7i-t) were explored for their antihyperglycemic potential and therefore evaluated for α-glucosidase and α-amylase inhibitory activities along with anti-inflammatory. The results suggest that among the series, compound 7l showed excellent activity with an IC50 value of 0.67±0.014 mg/mL and 0.72±0.012 mg/mL for α-amylase, and α-glucosidase inhibitory potential while compound 7o showed promising anti-inflammatory activity with IC50 value of 0.54±0.003 mg/mL. To support the above findings, molecular docking studies were performed, which confirmed the interaction of the synthesized molecules 7i-t with an effective binding energy of -9.0 to -10.6 kcal/mol at the active site of the enzyme human pancreatic α-amylase (PDB ID: 1B2Y). Therefore, these scaffolds have the potential to function as lead candidates for antidiabetic and anti-inflammatory activities.

Influence of Harvesting Stage on Phytochemical Composition, Antioxidant, and Antidiabetic Activity of Immature Ceratonia siliqua L. Pulp from Béni Mellal-Khénifra Region, Morocco: In Silico, In Vitro, and In Vivo Approaches.

Ceratonia siliqua L. is a medicinal plant that has long been used in traditional Moroccan medicine to treat many diseases. This study aimed to assess the impact of the stages of the immature phase of carob pulp (M1, M2, M3, M4, and M5) on phytochemical composition, antioxidant activity, and antidiabetic activity of Ceratonia siliqua L. The identification of the phenolic profile by HPLC-UV/MS-MS and the study of the antidiabetic effect by in silico, in vitro, and in vivo studies were carried out for extracts with high contents of phenolic compounds from immature wild carob pulp from the communes of Timoulit (TM), Bin Elouidane (AW), and Ouaouizerth (TG) in the province of Azilal in the Béni Mellal-Khénifra region. The results revealed a gradual increase in total sugar content over the pulp's ripening period, reaching a value of 2134 ± 56.23 mg GE/100 g fresh weight (FW) for TG. The three locations showed peak values for total polyphenol content (TPC), total flavonoid content (TFC), and total condensed tannin (TCT) at the M2 stage. AW had the highest concentrations of TPC (3819 ± 226.4 mg GAE/100 g FM), TFC (1034 ± 57.08 mg QE/100 g FM), and TCT (1472 ± 28.46 mg CE/100 g FM). The DPPH assay (7892 ± 296.1 mg TE/100 g FM) and the FRAP assay (278.2 ± 7.85 mg TE/100 g FM) both demonstrated that the TG zone is a highly potent antioxidant zone. In contrast, the AW site exhibited a markedly elevated value of 725.4 ± 103.6 mg TE/100 g FM in the ABTS assay. HPLC-UV-MS/MS analysis showed that the methanolic extracts of immature carob pulp (MEICP) from the three areas contained several different chemical compounds. The most prevalent were 3-O-p-coumaroyl-5-O-caffeoylquinic acid, quercetin 3-methyl ether, gallic acid, and galloylquinic acid. Immature carob pulp extract (ICPE) from AW showed the strongest in vitro inhibition of pancreatic α-amylase (IC50 = 0.405 µg/mL) and TG extracts were most potent against intestinal α-glucosidase (IC50 = 0.063 µg/mL). In vivo, AW, TG, and TM extracts significantly reduced postprandial glycemia in rats, with AW having the greatest effect. These results highlight the antidiabetic potential of ICPE. The 3-O-p-Coumaroyl-5-O-caffeoylquinic acid showed better affinity for α-amylase compared to acarbose and interacted significantly with several amino acid residues of the enzyme. Similarly, this molecule and 3,4-Dicaffeoylquinic acid demonstrated a strong affinity for α-glucosidase, suggesting their potential as natural inhibitors of enzymes involved in carbohydrate metabolism. Most of the compounds are not substrates of P-glycoprotein and exhibited high intestinal absorption. Furthermore, the majority of these compounds did not act as inhibitors or substrates of CYP450 enzymes, reinforcing their suitability for development as oral medications. These results underscore the potential of immature carob pulp as a promising antidiabetic agent.

Biodiversity in nutrients and biological activities of 14 highbush blueberry (Vaccinium corymbosum L.) cultivars

The present study aimed to identify nutrients (UPLC-PDA-ESI-MS/MS, HPLC-RI method) and biological activities (antioxidant activity to reduce Fe3+ and ABTS·+, pancreatic lipase inhibitory effect, α-amylase, and α-glucosidase, anti-bacterial) of 14 highbush blueberries (Vaccinium corymbosum L.) cultivars (Northern type) as well as a principal component analysis (PCA) to assess the variation of these properties in the context of biodiversity. Most of the cultivars in this research have been first presented in this paper. Phytochemical profiling of the tested highbush blueberry fruit revealed 75 bioactive compounds, including 5 macroelements, 7 microelements, 7 monophosphate nucleotides, 15 anthocyanins, 1 phenolic acid, 14 flavonols, 11 essential amino acids, 8 non-essential amino acids, 2 sugars, 7 organic acids. The PCA showed that the profile and contents of the analyzed compounds as well as their anti-bacterial, antioxidant, anti-diabetic, and anti-obesity potentials depended significantly on the tested cultivars. Thus, the study provides comprehensive data on cultivar-specific biodiversity and correlations that can be used to design novel extracts rich in polyphenolic, amino acids, and/or minerals extracts from the selected cultivars of highbush blueberry as natural and alternative sources to fulfill the growing industry demand for supplements, pharmaceuticals, and nutraceutical products.

PSLBI-9 The growth performance and total tract starch digestibility of finishing Nelore bulls fed flint corn-based diets are improved by the corn processing method and urea source

Abstract The aim of this study was to evaluate the flint corn processing method (CPM) and urea source for finishing Nellore bulls fed corn-based diets. In this study, 80 Nellore bulls [initial body weight (BW) = 388 ± 45.7 kg] were allocated into 28 pens (7 pens/treatment; 6 pens with 3 bulls + 1 pen with 2 bulls). A completely randomized design with a 2 × 2 factorial arrangement of treatments was used to test two CPMs: dry ground corn (DGC) and reconstituted and ensiled corn (REC), and two US: feed-grade urea (FGU) and post-ruminal release urea (PRU). Dietary inclusion (% DM) of flint corn (vitreousness = 86.0%) was 61.3% (DGC or REC), and urea source addition was 0.5% as non-protein nitrogen (NPN; as FGU or PRU). The PRU source (Trouw Nutrition, Netherlands) contained 82% urea on a DM basis. In an in vitro assay, 27% of this urea was released into the rumen. Experimental period lasted 100 d (with 14 d of adaptation). Fecal samples from each bull were collected in two periods of three consecutive days (d 44 to 46 and 94 to 96) at different time (0600, 1200, and 1800 h). Samples were composited by pen and analyzed for fecal starch (FS) and indigestible NDF as markers for fecal excretion. At the end of the experiment, bulls were slaughtered and the jejunum and pancreas were sampled from one bull per pen. Interaction effects were not found (P ≥ 0.31) for any feedlot growth performance variables (Table 1). Final BW, average daily gain, and feed efficiency (gain to feed; G:F) were greater for bulls fed REC and PRU than for those fed DGC and FGU (P < 0.02), respectively. As a result, observed dietary net energy (NE) for maintenance and BW gain were about 7.0% and 9.0% greater for bulls fed REC diets, and 4.3% and 5.6% greater for bulls fed PRU diets, respectively. Bulls fed DGC had 2.2 times greater FS compared with bulls fed REC, resulting in lower fecal pH and total tract starch digestibility (TSD) for bulls fed DGC compared with those fed REC (P < 0.01). Interestingly, a similar trend was observed in bulls fed PRU compared with those fed diets with FGU (P < 0.06). Jejunal gene expression of SLC5A1 was not affected by treatments (P > 0.14). Nevertheless, bulls fed diets with PRU presented greater jejunal α-amylase activity (P = 0.02). Pancreatic α-amylase activity was less when bulls were fed DGC + PRU diet. In conclusion, REC markedly improved TSD and growth performance compared with DGC. Additionally, independent of CPM, PRU inclusion as NPN source increased G:F and dietary NE concentration due to the positive effects on jejunal amylase activity and TSD.

Identification of pancreatin inhibitors from Thai medicinal Piper plants for antidiabetic and anti-obesity activities using high-performance thin-layer chromatography-bioautographic assay

Exploring the potential of natural products against diabetes and obesity is in demand nowadays. Pancreatic α-amylase and pancreatic lipase are the drug targets to minimize the absorption of glucose from starch and fatty acids from lipids, respectively. In this study, five Piper species, namely P. sarmentosum (Ps), P. wallichii (Pw), P. retrofractum (Pr), P. nigrum (Pn), and P. betle (Pb), which are commonly used as food ingredients and traditional medicines, were evaluated for their inhibitory activities against pancreatin using the microtiter plate method. Additionally, pancreatin inhibitors were identified through a cost-effective high-performance thin-layer chromatography (HPTLC)-bioautography developed using red starch and p-nitrophenyl palmitate, corresponding to anti-amylase and -lipase activities, respectively. Of the 15 samples tested, leaf samples from Pb, which had the highest total phenolic and total flavonoid contents, exhibited remarkable inhibitory activity against pancreatin, with a relative amylase inhibitory capacity (RAIC) ranging between 4.260 × 10−5 and 4.861 × 10−5 and a reciprocal half-maximal inhibitory concentration (1/IC50, PTL) of 0.390–0.510 (mg/mL)−1. Additionally, Ps samples demonstrated the second-ranked anti-pancreatin activity. Principal component analysis indicated that total phenolic content contributed to the anti-pancreatin activities of Pb samples. The anti-pancreatin bands were isolated and identified as caffeic acid, myricetin, genistein, piperine, and eugenol. Myricetin, in the roots of Ps samples, showed notable anti-pancreatin activity, which was consistent with results from the in silico prediction toward pancreatic α-amylase and pancreatic lipase. Caffeic acid and eugenol were present in Pb samples. In conclusion, the developed cost-effective pancreatin HPTLC-bioautography efficiently identified amylase and lipase inhibitors from Piper herbs, which supported the use of these plants for antidiabetes and anti-obesity.

Dual amylase/glucosidase inhibition, antilipolytic and antiproliferative potential of the aerial parts of Pistacia atlantica, Pistacia lentiscus and Pistacia terebinthus on a obesity related-colorectal cancer cell line panel

Abstract Pistacia species (P. spp) have been used as a treatment for various diseases, including diabetes and inflammation. This study aimed to identify the main components of flavonoids in Pistacia species and evaluate the effect of aqueous extracts of P. spp on pancreatic enzymes and on cancer cells associated with obesity in colon and rectum. HPLC was used to identify the major components of flavonoids. The potent inhibitory effect of Pistacia species against pancreatic α-amylase, α-glucosidase and lipase was examined. The antiproliferative efficacy of the plant extract against several colorectal cancer cell lines were then measured. The main flavonoids component found in Pistacia species are quercetin-3-β-D-glucoside, rutin, kaempferol and vitexin. The starch blockade IC50 (µg/mL) of Pistacia species in a descending order were: P. lentiscus leaves: 1.09±0.01; P. atlantica leaves: 0.96±0.09 and P. atlantica fruits: 0.48±0.02. Pistacia species exerted promising inhibition effect for pancreatic lipase (PL). Besides the aglycones of P. atlantica leaves, all the tested aqueous extracts exerted appreciably novel antiproliferative activity against the tested colorectal cancer cell lines. This study provides useful indication for the Pistacia species as a potential novel therapeutic agent against diabesity and cancer.

Fluoride-Induced Alterations in the Pancreas of Mammals: A Meta-analysis.

This review explores the diverse effects of fluoride on pancreatic function, encompassing both in vitro and in vivo studies. Fluoride exposure induces notable alterations at the cellular and molecular levels, affecting pancreatic morphology, histology, and enzymatic activity. In vitro studies demonstrate significant inhibition of pancreatic α-amylase activity and apoptosis in pancreatic beta cells. In vivo investigations reveal structural abnormalities in pancreatic cells, including mitochondrial damage, vacuolation, and nuclear damage. Moreover, fluoride exposure disrupts antioxidant enzyme activity, exacerbating oxidative stress and lipid peroxidation. Changes in digestive enzyme activity, such as the inhibition of pancreatic lipase and α-amylase, further contribute to pancreatic dysfunction. Additionally, alterations in hormone secretion, notably insulin levels and disturbed glucose homeostasis, highlight the complex effects of fluoride on the pancreatic endocrine system. These findings underscore fluoride-induced pancreatic toxicity and highlight the need for a comprehensive understanding and mitigation strategies to safeguard pancreatic health.

Assessing anti oxidant, antidiabetic potential and GCMS profiling of ethanolic root bark extract of Zanthoxylum rhetsa (Roxb.) DC: Supported by in vitro, in vivo and in silico molecular modeling.

Zanthoxylum rhetsa (ZR) is used traditionally to manage a variety of ailments, including diabetes. Oxidative stress may accelerate the diabetic condition. The available antidiabetic and antioxidant drugs have many shortcomings including resistance, inefficiency, higher dose, side effects and costs. The goal of the current investigation was to assess the antioxidant capacity and antidiabetic activity of an ethanolic extract of Zanthoxylum rhetsa root bark (ZRRB) through in vitro, in vivo, and in silico methods. The antioxidant capacity of the ZRRB extract was measured using both the DPPH radical assay and the total antioxidant activity test. The oral glucose tolerance test (OGTT) and alloxan-induced diabetic mice model were also used to examine in vivo antidiabetic efficacy. Phytochemicals identification was done by GCMS analysis. Additionally, computational methods such as molecular docking, ADMET analysis, and molecular dynamics (MD) modeling were performed to determine the above pharmacological effects. The extract demonstrated significant DPPH scavenging activity (IC50 = 42.65 μg/mL). In the OGTT test and alloxan-induced diabetes mice model, the extract effectively lowered blood glucose levels. Furthermore, in vitro inhibition of pancreatic α-amylase studies demonstrated the ZRRB extract as a good antidiabetic crude drug (IC50 = 81.45 μg/mL). GCMS investigation confirmed that the crude extract contains 16 major phytoconstituents, which were docked with human peroxiredoxin-5, α-amylase, and sulfonylurea receptor 1. Docking and pharmacokinetic studies demonstrated that among 16 phytoconstituents, 6H-indolo[3,2,1-de] [1,5]naphthyridin-6-one (CID: 97176) showed the highest binding affinity to targeted enzymes, and imitated Lipinski's rule of five. Furthermore, MD simulation data confirmed that the aforementioned compound is very steady to the binding site of α-amylase and sulfonylurea receptor 1 receptors. Findings from in vitro, in vivo and in silico investigation suggest that ZRRB extract contains a lead compound that could be a potent source of antidiabetic drug candidate.

Indole–thiazolidinedione–triazole hybrids: synthesis, molecular docking, absorption, distribution, metabolism and excretion (ADME) profiling, and biological evaluation as α-amylase inhibitors

Abstract A novel series of hybrid indole–thiazolidinedione–triazole derivatives (6a-l) were synthesized and assessed for their in vitro inhibitory activity against porcine pancreatic α-amylase. The synthetic procedure consists of 3 steps. A crucial step in this process involves the generation of novel target molecules using a Cu(I)-catalyzed azide–alkyne cycloaddition reaction. The α-amylase inhibition IC50 value of the targeted compounds ranged from 0.51 ± 0.02 to 7.99 ± 0.28 μM as compared with 0.68 ± 0.02 μM with acarbose as the standard drug. Using the Autodock technique, all the derivatives 6a-l were subjected to molecular docking investigations against porcine pancreatic α-amylase (PDB ID: 1OSE). Moreover, it was discovered that the docked compounds had excellent binding affinities that ranged from −10.1 to −10.8 kcal/mol as compared with the standard −7.9 kcal/mol. Additionally, a comprehensive analysis of the physicochemical and pharmacokinetic properties associated with absorption, distribution, metabolism and excretion (ADME) was conducted for all the synthesized compounds.

Ultrasound-assisted synthesis of 4-thiazolidinone Schiff bases and their antioxidant, α-glucosidase, α-amylase inhibition, mode of inhibition and computational studies

AbstractDiabetes mellitus (DM) has become a growing concern to global public health, being at the forefront of acute disorders and causes of mortality across the globe. Clinically approved drugs that are currently being used are faced with severe side effects, consequently necessitating the development of new drugs with no/fewer side effects and improved pharmacological potency. Herein, we report a rapid and efficient synthesis of thiazolidinone Schiff bases (2a-2t) from benzylidenehydrazines and thioglycolic acid under neat conditions through ultra-sonication. All the synthesized compounds were obtained in exceptional yields (89–95%) and confirmed by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, as well as High-resolution mass spectrometry (HRMS). The synthesized compounds were then evaluated for their antidiabetic activity through α-glucosidase and α-amylase inhibitory potentials and their antioxidant activity through Nitric Oxide (NO), 2,2′-diphenyl-1-picrylhydrazyl (DPPH), and Ferric reducing antioxidant power (FRAP) assays. Among them, 2q (IC50 = 96.63 μM) and 2h (IC50 = 125.27 μM) emerged as the most potent derivatives against α-amylase relative to reference drug acarbose (IC50 = 131.63 µM), respectively. Antioxidant evaluation further revealed that the synthesized derivatives were excellent NO scavengers disclosing 2n (IC50 = 44.95 µM) as the most potent derivative. Moreover, in silico ADME calculations predicted these compounds to have excellent drug-like properties. Kinetic studies disclosed the mode of α-amylase inhibition as competitive while molecular docking studies of the most active derivatives performed into the binding active site of human pancreatic α-amylase enzyme deciphered their ligand-protein interactions that explicated their observed experimental potencies.

Virtual screening, ADME prediction, drug-likeness, and molecular docking analysis of Fagonia indica chemical constituents against antidiabetic targets.

Fagonia indica from Zygophyllaceae family is a medicinal specie with significant antidiabetic potential. The present study aimed to investigate the in vitro antidiabetic activity of Fagonia indica crude extract followed by an in silico screening of its phytoconstituents. For this purpose, crude extract of Fagonia indica was prepared and divided in three different parts, i.e., n-hexane, ethyl acetate, and methanolic fraction. Based on in vitro outcomes, the phytochemical substances of Fagonia indica were virtually screened through a literature survey and a screening library of compounds (1-13) was prepared. The clinical potential of these novel drug candidates was assessed by applying an ADME screening profile. Findings of SwissADME indicators (Absorption, Distribution, Metabolism, and Excretion) for the compounds (1-13) presented relatively optimal physicochemical characteristics, drug-likeness, and medicinal chemistry. The antidiabetic action of these leading drug candidates was optimized through molecular docking analysis against 3 different human pancreatic α-amylase macromolecular targets with (PDB ID 1B2Y), (PDB ID 3BAJ), and (PDB ID: 3OLI) by applying Virtual Docker (Molegro MVD). Metformin was taken as a reference standard for the sake of comparison. In vitro antidiabetic evaluation gave good results with promising α-amylase inhibitory action in the form of IC50 values, as for n-hexane extract = 206.3µM, ethyl acetate = 41.64µM, and methanolic extract = 9.61µM. According to in silico outcomes, all 13 phytoconstituents possess the best binding affinity with successful MolDock scores ranging from - 97.2003 to - 65.6877kcal/mol and show a great number of binding interactions than native drug metformin. Therefore, the current work concluded that the diabetic inhibition prospective of extract and the compounds of Fagonia indica may contribute to being investigated as a new class of antidiabetic drug or drug-like candidate for further studies.

Design, Synthesis of 3-(Aryl)-1-(2-p-tolylthiazol-4-yl)prop-2-en-1-ones as Alpha(α)-Amylase Inhibitors.

α-Amylase inhibition is vital in controlling diabetic complications. Herein, we have synthesized a hybrid scaffold based on thiazole-chalcone to access α-amylase inhbition. The proposed structures were verified with spectroscopic techniques (UV-Vis., FT-IR, 1H-, 13C-NMR, and elemental analysis). The synthesized compounds were evaluated for their α-amylase and antioxidant potential. In vitro hemolytic assay was performed to test biocompatibility of all compounds. Among tested compounds, 4 c (IC50=3.8 μM), 4 g (IC50=14.5 μM), and 4 f (IC50=17.1 μM) were found excellent α-amylase inhibitors. However, none of the tested compounds exhibited significant antioxidant activity. All compounds showed less lysis than Triton X-100, but compounds 4 f and 4 h had the least lysis at all tested concentrations and were found to be safe for human erythrocytes. Molecular docking study was performed to evaluate the binding interactions of ligands with human pancreatic α-amylase (HPA). The binding score -8.09 to -8.507 kcal/mol revealed strong binding interactions in the ligand-protein complex. The docking results supplemented the observed α-amylase inhibition and hence augment the scaffold to serve as leads for the antidiabetic drug development.

Synthesis and In Silico Analysis of New Polyheterocyclic Molecules Derived from [1,4]-Benzoxazin-3-one and Their Inhibitory Effect against Pancreatic α-Amylase and Intestinal α-Glucosidase.

This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a-5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a "click chemistry" approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of -9.9 and -9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski's criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development.