Promising Α-glucosidase Research Articles

Employing Machine Learning Models to Predict Potential α-Glucosidase Inhibitory Plant Secondary Metabolites Targeting Type-2 Diabetes and Their In Vitro Validation.

The need for new antidiabetic drugs is evident, considering the ongoing global burden of type-2 diabetes mellitus despite notable progress in drug discovery from laboratory research to clinical application. This study aimed to build machine learning (ML) models to predict potential α-glucosidase inhibitors based on the data set comprising over 537 reported plant secondary metabolite (PSM) α-glucosidase inhibitors. We assessed 35 ML models by using seven different fingerprints. The Random forest with the RDKit fingerprint was the best-performing model, with an accuracy (ACC) of 83.74% and an area under the ROC curve (AUC) of 0.803. The resulting robust ML model encompasses all reported α-glucosidase inhibitory PSMs. The model was employed to predict potential α-glucosidase inhibitors from an in-house 5810 PSM database. The model identified 965 PSMs with a prediction activity ≥0.90 for α-glucosidase inhibition. Twenty-four predicted PSMs were subjected to in vitro assay, and 13 were found to inhibit α-glucosidase with IC50 ranging from 0.63 to 7 mg/mL. Among them, seven compounds recorded IC50 values less than the standard drug acarbose and were investigated further to have optimal drug-likeness and medicinal chemistry characteristics. The ML model and in vitro experiments have identified nervonic acid as a promising α-glucosidase inhibitor. This compound should be further investigated for its potential integration into the diabetes treatment system.

A promising α-glucosidase and α-amylase inhibitors based on benzimidazole-oxadiazole hybrid analogues: Evidence based in vitro and in silico studies

The present study reports the design and synthesis of new benzimidazole-oxadiazole compounds as potent inhibitors of α-glucosidase and α-amylase. The synthesized molecules were characterized through different techniques such as 1HNMR, 13CNMR, HREI-MS and evaluated for their in vitro inhibitory activities against these enzymes. Among the compounds screened, compound 8 demonstrated the highest inhibitory activity against both α-glucosidase (IC50 = 11.60 µM) and α-amylase (IC50 = 6.20 µM). Molecular docking analyses were conducted to investigate the binding modes and interactions of the active compounds within the enzyme active sites. The results demonstrate that several benzimidazole-oxadiazole hybrids exhibited potent inhibitory effects on both α-glucosidase and α-amylase, suggesting their promise as antidiabetic agents.

Optimization of subcritical water extraction, UPLC–triple–TOF–MS/MS analysis, antioxidant and α-glucosidase inhibitory activities of anthocyanins from Nitraria sibirica Pall. fruits

This study aimed to optimize subcritical water extraction process, characterize chemical composition and investigate the biological activities of Nitraria sibirica Pall. (NSP) anthocyanin. Overall, the optimization was achieved under following conditions: extraction temperature 140 °C, extraction time 45 min and flow rate 7 mL/min with the extraction yield of 1.075 mg/g. 3 cyanidin, 3 petunidin, 1 delphinidin and 1 pelargonidin compounds were identified in the anthocyanic extract from NSP via UPLC–Triple–TOF–MS/MS. NSP anthocyanin exhibited better DPPH free-radical scavenging activity than ascorbic acid. It displayed superior α-glucosidase inhibition activity, which was ∼14 times higher than that of acarbose. Moreover, enzyme kinetics results indicated that NSP anthocyanin behaved as a reversible, mixed-type inhibitor. Molecular docking and molecular dynamics simulation results revealed that NSP anthocyanin interacted with α-glucosidase mainly via van der Waals forces, hydrogen bond and possessed fairly stable configuration. Therefore, NSP anthocyanin is a promising α-glucosidase inhibitor for diabetes mellitus.

Synthesis of the chromone-thiosemicarbazone scaffold as promising α-glucosidase inhibitors: An in vitro and in silico approach towardantidiabetic drug design.

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 μM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 μM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.

Synthesis,Antidiabetic and Antitubercular Evaluation of Quinoline-pyrazolopyrimidine hybrids and Quinoline-4-Arylamines.

Two libraries of quinoline-based hybrids 1-(7-chloroquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 7-chloro-N-phenylquinolin-4-amine were synthesized and evaluated for their α-glucosidase inhibitory and antioxidant properties. Compounds with 4-methylpiperidine and para-trifluoromethoxy groups, respectively, showed the most promising α-glucosidase inhibition activity with IC50=46.70 and 40.84 μM, compared to the reference inhibitor, acarbose (IC50=51.73 μM). Structure-activity relationship analysis suggested that the cyclic secondary amine pendants and para-phenyl substituents account for the variable enzyme inhibition. Antioxidant profiling further revealed that compounds with an N-methylpiperazine and N-ethylpiperazine ring, respectively, have good DPPH scavenging abilities with IC50=0.18, 0.58 and 0.93 mM, as compared to ascorbic acid (IC50=0.05 mM), while the best DPPH scavenger is NO2-substituted compound (IC50=0.08 mM). Also, compound with N-(2-hydroxyethyl)piperazine moiety emerged as the best NO radical scavenger with IC50=0.28 mM. Molecular docking studies showed that the present compounds are orthosteric inhibitors with their quinoline, pyrimidine, and 4-amino units as crucial pharmacophores furnishing α-glucosidase binding at the catalytic site. Taken together, these compounds exhibit dual potentials; i. e., potent α-glucosidase inhibitors and excellent free radical scavengers. Hence, they may serve as structural templates in the search for agents to manage Type 2 diabetes mellitus. Finally, in preliminary assays investigating the anti-tubercular potential of these compounds, two pyrazolopyrimidine series compounds and a 7-chloro-N-phenylquinolin-4-amine hybrid showed sub-10 μM whole-cell activities against Mycobacterium tuberculosis.

Nicotinonitriles as potential inhibitors of α-glucosidase, tyrosinase, and urease enzymes: Synthesis, characterization, in vitro, and in silico studies

In an effort to develop novel enzyme inhibitors with potent activity and high selectivity, a series of nicotinonitrile derivatives was synthesized. Cyano pyridone intermediates undergo nucleophilic substitution reactions with variously substituted phenacyl halides to yield the nicotinonitriles 1–20. All nicotinonitriles exhibited moderate to excellent in vitro enzyme inhibitory activities against α-glucosidase, tyrosinase, and urease. Compound 1 (IC50 = 27.09 ± 0.12 µM) selectively displayed more significant activity than the standard acarbose (IC50 = 40.00 ± 0.70 µM). Compound 1 also showed good urease inhibition (IC50 = 33.04 ± 0.70 µM); however, it exhibited activity less than the standard acetohydroxamic acid (IC50 = 27.00 ± 0.50 µM).Furthermore, the most effective compound of the series against tyrosinase compared to the standard kojic acid (IC50 = 16.9 ± 1.30 µM) was 16 with an IC50 value of 10.55 ± 0.08 µM. In contrast, this compound showed no activity against α-glucosidase and urease. DFT calculations were carried out to analyze electronic transitions and energy levels (HOMO and LUMO) in nicotinonitrile derivatives, offering insights into their chemical reactivity and stability. Molecular docking studies and molecular electrostatic potential (MEP) revealed the interactions of the active compounds with the amino acid residues at the active sites of the enzymes, thereby shedding light on the mechanism of enzyme inhibition. Therefore, compound 1 can be further studied as a promising α-glucosidase and urease inhibitor, while compound 16 is an effective tyrosinase inhibitor.

Photoredox-catalyzed bisarylation of Bromonitroalkanes enabled by the dual role of nitro functionality: synthesis of bis(indolyl)methanes as promising α-glucosidase inhibitors

Disclosed herein is an interesting photoredox catalyzed direct bisarylation of Bromonitroalkanes with 2-Arylindoles to provide a simplified synthetic route to 3,3'-Diindolylmethane (DIM) derivatives, where the nitro functionality plays a dual...

Discovery of N-(phenylsulfonyl)thiazole-2-carboxamides as potent α-glucosidase inhibitors.

In a search for novel nonsugar α-glucosidase inhibitors for diabetes treatment, a series of N-(phenylsulfonyl)thiazole-2-carboxamide derivatives were designed and synthesized, the α-glucosidase inhibitory activities were then evaluated. Several compounds with promising α-glucosidase inhibitory effects were identified. Among these, compound W24 which shows low cytotoxicity and good α-glucosidase inhibitory activity with an IC50 value of 53.0 ± 7.7 μM, is more competitive compared with the commercially available drug acarbose (IC50 = 228.3 ± 9.2 μM). W24 was identified as a promising candidate in the development of α-glucosidase inhibitors. Molecular docking studies and molecular dynamics simulation were also performed to reveal the binding pattern of the active compound to α-glucosidase, and the binding free energy of the best compound W24 was 36.3403 ± 3.91 kcal/mol.

Deciphering Molecular Aspects of Potential α-Glucosidase Inhibitors within Aspergillus terreus: A Computational Odyssey of Molecular Docking-Coupled Dynamics Simulations and Pharmacokinetic Profiling.

Hyperglycemia, as a hallmark of the metabolic malady diabetes mellitus, has been an overwhelming healthcare burden owing to its high rates of comorbidity and mortality, as well as prospective complications affecting different body organs. Available therapeutic agents, with α-glucosidase inhibitors as one of their cornerstone arsenal, control stages of broad glycemia while showing definitive characteristics related to their low clinical efficiency and off-target complications. This has propelled the academia and industrial section into discovering novel and safer candidates. Herein, we provided a thorough computational exploration of identifying candidates from the marine-derived Aspergillus terreus isolates. Combined structural- and ligand-based approaches using a chemical library of 275 metabolites were adopted for pinpointing promising α-glucosidase inhibitors, as well as providing guiding insights for further lead optimization and development. Structure-based virtual screening through escalating precision molecular docking protocol at the α-glucosidase canonical pocket identified 11 promising top-docked hits, with several being superior to the market drug reference, acarbose. Comprehensive ligand-based investigations of these hits' pharmacokinetics ADME profiles, physiochemical characterizations, and obedience to the gold standard Lipinski's rule of five, as well as toxicity and mutagenicity profiling, proceeded. Under explicit conditions, a molecular dynamics simulation identified the top-stable metabolites: butyrolactone VI (SK-44), aspulvinone E (SK-55), butyrolactone I 4''''-sulfate (SK-72), and terrelumamide B (SK-173). They depicted the highest free binding energies and steadiest thermodynamic behavior. Moreover, great structural insights have been revealed, including the advent of an aromatic scaffold-based interaction for ligand-target complex stability. The significance of introducing balanced hydrophobic/polar moieties, like triazole and other bioisosteres of carboxylic acid, has been highlighted across docking, ADME/Tox profiling, and molecular dynamics studies for maximizing binding interactions while assuring safety and optimal pharmacokinetics for targeting the intestinal-localized α-glucosidase enzyme. Overall, this study provided valuable starting points for developing new α-glucosidase inhibitors based on nature-derived unique scaffolds, as well as guidance for prospective lead optimization and development within future pre-clinical and clinical investigations.

In vitro evaluation of novel mefenamic acid derivatives as potential α-glucosidase and urease inhibitors: Design, synthesis, in silico and cytotoxic studies

This study aim to synthesize new 1,3,4-oxadiazole derivatives incorporating mefenamic acid as promising α-glucosidase and urease inhibitors, potentially leading to the treatment of postprandial hyperglycemia as well as H. pylori related disorders. In this regards, we have designed a series of Mefenamic acid derivatives. The synthetic compounds were structurally elucidated through 1H NMR, 13C NMR and HR-EIMS analysis. The biological evaluation of these derivatives against α-glucosidase and urease enzyme depicted some novel derivatives with potent inhibition against the said enzymes. All the derivatives exhibited potent inhibition against α-glucosidase enzymes with IC50 ranging from 25.81 ± 1.63–113.61 ± 1.31 µM against standard drug acarbose (IC50 = 375.82 ± 1.76 µM) while with respect to urease these derivatives possessed inhibitory potential varied between IC50 = 8.04 ± 1.01–58.18 ± 1.03 µM against the standard thiourea (IC50 = 21.0 ± 1.76 µM). The cell viability results revealed that all of the derivatives were found least cytotoxic. Furthermore, molecular docking studies of the most potent derivatives identify number of key features involved in binding interactions between potential inhibitors and the enzyme's active site.

Metabolic profiling, antioxidant, and enzyme inhibition potential of Iris pseudacorus L. from Egypt and Japan: A comparative study

Genus Iris comprises numerous and diverse phytoconstituents displaying marked biological activities. The rhizomes, and aerial parts of Iris pseudacorus L. cultivars from Egypt and Japan were subjected to comparative metabolic profiling using UPLC-ESI-MS/MS. The antioxidant capacity was determined using DPPH assay. In vitro enzyme inhibition potential against α-glucosidase, tyrosinase and lipase was evaluated. In silico molecular docking was conducted on the active sites of human α-glucosidase and human pancreatic lipase. Forty-three compounds were tentatively identified including flavonoids, isoflavonoids, phenolics and xanthones. I. pseudacorus rhizomes extracts (IPR-J and IPR-E) exhibited the highest radical scavenging activity with IC50 values of 40.89 µg/mL and 97.97 µg/mL, respectively (Trolox IC50 value was 14.59 µg/mL). Moreover, IPR-J and IPR-E exhibited promising α-glucosidase inhibitory activity displaying IC50 values of 18.52 µg/mL, 57.89 µg/mL, respectively being more potent as compared to acarbose with IC50 value of 362.088 µg/mL. All extracts exerted significant lipase inhibitory activity exhibiting IC50 values of 2.35, 4.81, 2.22 and 0.42 µg/mL, respectively compared to cetilistat with IC50 value of 7.47 µg/mL. However, no tyrosinase inhibitory activity was observed for all I. pseudacorus extracts up to 500 µg/mL. In silico molecular modelling revealed that quercetin, galloyl glucose, and irilin D exhibited the highest fitting scores within the active sites of human α-glucosidase and pancreatic lipase. ADMET prediction (absorption, distribution, metabolism, excretion, and toxicity) showed that most of the phytoconstituents exhibited promising pharmacokinetic, pharmacodynamics and tolerable toxicity properties. According to our findings, I. pseudacorus might be considered as a valuable source for designing novel phytopharmaceuticals.

Iridoid- and flavonoid-enriched fractions of Cornus sanguinea and Cornus mas exert antioxidant and anti-inflammatory effects and inhibit key enzymes in the treatment of metabolic disorders.

Background: Berry fruits are recognized as a "superfood" due to their high content of bioactive compounds and health benefits. Scope and approach: Herein, extracts of Cornus sanguinea and Cornus mas fresh and dried fruits obtained by different extraction procedures (ethanolic and hydroalcoholic maceration, ultrasound-assisted extraction, and Soxhlet apparatus) were analysed using liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-QTOF-MS) and compared to identify the main healthy compounds and their impact on the inhibition of key enzymes (pancreatic lipase, α-glucosidase, and α-amylase) associated with metabolic disorders. The antioxidant activity and inhibition of nitric oxide (NO) and NF-κB pathway were also investigated. Key findings and conclusions: Flavonoids, iridoids, and phenolic acids were the main classes of identified compounds. Herein, kaempferol 3-O-galactoside, kaempferol 3-O-glucoside, quercetin, quercetin 3-O-xyloside, and myricetin 3-O-galactoside were detected for the first time in C. sanguinea. Remarkable antioxidant effects and promising α-glucosidase and lipase inhibitory activity were observed with extracts obtained by hydroalcoholic maceration of both Cornus dried fruits. Consequently, these extracts were subjected to fractionation using Amberlite XAD-16 resin. The most promising biological activities, which are attributed to the presence of some flavonoids and iridoids, were detected with the C. sanguinea fractions, in particular SD2(II). The results of this study offer new insights into the potential development of functional foods, nutraceuticals, and food supplements using the Cornus species.

Oligomeric Proanthocyanidin Complex from Avocado Seed as A Promising α-glucosidase Inhibitor: Characteristics and Mechanisms.

Although considered an abundant source of agricultural by-products, avocado (Persea americana Mill.) seed, with several biological activities and bioactive components, might become a promising resource for phytopharmaceutical development. In this study, through bioassay-guided isolation of the main α-glucosidase inhibitors in avocado seed, we discovered the major α-glucosidase inhibitor to be avocado seed oligomeric proanthocyanidin complex (ASOPC). Thiolysis and UPLC-DAD-HRESIMS showed the presence of A- and B-type procyanidins, and B-type propelargonidin with (epi)afzelechin as extension unit. Mean degree of polymerization (mDP) of ASOPC was calculated as 7.3 ± 1. Furthermore, ASOPC appeared to be a strong, reversible, competitive inhibitor of α-glucosidase, with IC50 value of 0.1 µg/mL, which was significantly lower than Acarbose (IC50 = 75.6 µg/mL), indicated that ASOPC is a potential natural α-glucosidase inhibitor. These findings would contribute to the direction of utilizing avocado seed bioactive components with the possibility to be used as natural anti-diabetic agents.

Bioactive polyketide derivatives from the endophytic fungus Phaeosphaeriopsis musa

Two undescribed phenolic derivatives musaones A and B, six undescribed γ-butyrolactone musaolides A-F, together with two undescribed cyclopentanone musaolides G and H were isolated from the solid culture of an endophytic strain Phaeosphaeriopsis musae M. Arzanlou & Crous (Phaeosphaeriaceae). Their structures were unambiguously elucidated by extensive spectral analyses. The absolute configurations of two diastereomers musaolides G and H were assigned by comparing their experimental and calculated ECD data. Moreover, the in vitro α-glucosidase inhibition and cytotoxic activities of isolated compounds (except musaolide D) were evaluated to understand their biological effects, wherein musaone B and musaolide F displayed promising α-glucosidase inhibition with IC50 values of 37.3 ± 0.59 μM and 105.18 ± 2.76 μM respectively, compared to the positive control acarbose (24.99 ± 1.28 μM).

Cytotoxic and α-Glucosidase Inhibitory Xanthones from Garcinia mckeaniana Leaves and Molecular Docking Study.

A new racemic xanthone, garmckeanin A (1), and eight known analogs 2-9 were isolated from the ethyl acetate (AcOEt) extract of the Vietnamese Garcinia mckeaniana leaves. Their structures were determined by MS and NMR spectral analyses and compared with the literature. The AcOEt extract showed good cytotoxicity against cancer cell lines KB, Lu, Hep-G2 and MCF7, with IC50 values of 5.40-8.76 μg/mL, and it also possessed α-glucosidase inhibitory activity, with an IC50 value of 9.17 μg/mL. Garmckeanin A (1) exhibited inhibition of all cancer cell lines, with an IC50 value of 7.3-0.9 μM. Allanxanthone C (5) successfully controlled KB growth, with an IC50 value of 0.54 μM, higher than that of the positive control, ellipticine (IC50 1.22 μM). Norathyriol (8) was a promising α-glucosidase inhibitor, with an IC50 value of 0.07 μM, much higher than that of the positive control, acarbose (IC50 161.0 μM). The interactions of the potential α-glucosidase inhibitors with the C- and N-terminal domains of human intestinal α-glucosidase were also investigated by molecular docking study. The results indicated that bannaxanthone D (2), garcinone E (4), bannaxanthone E (6), and norathyriol (8) exhibit higher binding affinity to the C-terminal than to the N-terminal domain through essential residues in the active sites. In particular, compound 8 could be assumed to be the most potent mixed inhibitor.

Multicomponent reaction for the synthesis of new 1,3,4-thiadiazole-thiazolidine-4-one molecular hybrids as promising antidiabetic agents through α-glucosidase and α-amylase inhibition

A simple and efficient protocol was developed to synthesize a new library of thiazolidine-4-one molecular hybrids (4a-n) via a one-pot multicomponent reaction involving 5-substituted phenyl-1,3,4-thiadiazol-2-amines, substituted benzaldehydes and 2-mercaptoacetic acid. The synthesized compounds were evaluated in vitro for their antidiabetic activities through α-glucosidase and α-amylase inhibition as well as their antioxidant and antimicrobial potentials. Compound 4e exhibited the most promising α-glucosidase and α-amylase inhibition with an IC50 value of 2.59 μM, which is ~1.5- and 14-fold superior as compared to the standard inhibitor acarbose. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the phenyl rings had a significant effect on the inhibitory potency.

Synthesis, in vitro and computational studies of novel glycosyl-1, 2, 3-1H-triazolyl methyl benzamide derivatives as potential α-glucosidase inhibitory activity

A series of novel glycosyl-1,2,3-1H-triazolyl methyl benzamide analogues were synthesized by the unambiguous strategy and evaluated for α-glucosidase inhibitory activity. Glycosyl benzamide exhibited a dose-dependent inhibition of α-glucosidase activity. The In-vitro α-glucosidase inhibition activity results indicated that all the synthesized triazolyl methyl benzamide compounds (IC50 values ranging from 25.3 ± 0.8 to 118.5 ± 5.3 μM) exhibited more inhibitory activity in comparison with the standard drug acarbose (IC50 = 750.0 ± 12.5 μM). Among all, the 3 deacetylated glycosyl methyl benzamide derivatives (4c, 4d and 4f) showed promising α-glucosidase enzyme inhibitory activities with IC50 value 25.3 ± 0.8, 26.1 ± 1.5 and 30.6 ± 2.1 respectively. Furthermore, these compounds were subjected to molecular docking and molecular dynamics simulation studies. The molecular docking studies were performed between (PDB ID: 3A4A) target protein and these synthesized molecules. The compounds displayed good docking energies in the range of −7.5 to −7.8 Kcal/mol. This work could be used as an initial approach in identifying potential novel molecules with the promising activity of type-2 diabetes mellitus.

Oleanolic acid indole derivatives as novel α-glucosidase inhibitors: Synthesis, biological evaluation, and mechanistic analysis

Research efforts have been directed to the development of oleanolic acid (OA) based α-glucosidase inhibitors and various OA derivatives showed improved anti-α-glucosidase activity. However, the inhibitory effects of indole infused OA derivatives on α-glucosidase is unknown. Herein, we synthesized a series of indole-OA (2a-2o) and -OA methyl ester (3a-3 l) derivatives with various electron withdrawing groups inducted to indole benzene ring and evaluated their anti-α-glucosidase activity. Indole OA derivatives (2a-2o) exhibited superior α-glucosidase inhibitory effects as compared to OA methyl ester derivatives (3a-3l) and OA (with IC50 values of 4.02 μM-5.30 μM v.s. over 10 μM and 5.52 µM, respectively). In addition, mechanistic studies using biochemical (kinetic assay), biophysical (circular dichroism), and computational (docking) methods revealed that OA-indole derivatives (2a and 2f) are mixed type of α-glucosidase inhibitors and their inhibitory effects were attributed to their capacity of forming the ligand-enzyme complex with α-glucosidase enzyme. Findings from this study support that OA indole derivatives are promising α-glucosidase inhibitors as a potential management of diabetes mellitus.

Conventional and Non-Conventional Targets of Natural Products in the Management of Diabetes Mellitus and Associated Complications.

Diabetes Mellitus (DM) is a severe endocrine metabolic disease coupled with various long-term complications. A plethora of targets have been identified, however, with possible adverse effects. Therefore, researchers are in the perpetual quest for safe and more effective therapeutics. Natural products, particularly derived from plants, have proven to exert anti-diabetic effects via diverse mechanisms. An overview of DM pathogenesis and its associated micro- and macro-vascular complications is presented. Possible underlying mechanisms of herbal remedies in DM management are provided, highlighting some key therapeutic targets. The review also appraises the recent progress of herbal products in treating DM through regulating inflammation and gut microbiota. Finally, currently available pharmacological treatments are discussed. The results show that numerous plants have proven to be promising sources of insulin secreting agents, α-glucosidase and α-amylase inhibitors. Among the non- conventional targets, inhibition of key enzymes such as lipase, cholinesterases and angiotensin converting enzyme has been directly and/or indirectly linked to DM and DM complications. For instance, hypericin, pseudohypericin and I3,II8-biapigenin isolated from Hypericum perforatum L., and palmatine and columbamine isolated from Dichocarpum auriculatum (Franch.) W. T. Wang & P. K have been found to be powerful lipase and cholinesterase inhibitors, respectively. Moreover, a number of plant-derived compounds such as feruloylated oligosaccharides from maize bran, baicalein and berberine are reported to mediate anti-diabetic property via modulation of gut microbiota. The information amassed in this review is anticipated to provide useful scientific baseline information to support advanced research in natural antidiabetic drug development.

Discovery, biological evaluation and docking studies of novel N-acyl-2-aminothiazoles fused (+)-nootkatone from Citrus paradisi Macf. as potential α-glucosidase inhibitors

Nowadays, the discovery and development of α-glucosidase inhibitors from natural products or their derivatives represents an attractive approach. Here we reported studies on a series of novel N-acyl-2-aminothiazoles fused (+)-nootkatone and evaluation for their α-glucosidase inhibitory activities. Most of (+)-nootkatone derivatives exhibited more potent α-glucosidase inhibitory ability than the positive drug acarbose. In particular, compounds II7 and II14 showed the most promising α-glucosidase inhibitory ability with IC50 values of 13.2 and 13.8 µM. II7 and II14 also exhibited relatively low cytotoxicities towards normal LO2 cells. Kinetic study indicated that compounds II7 and II14 inhibited the α-glucosidase in a noncompetitive manner, and molecular docking results were in line with the noncompetitive characteristics that II7 and II14 did not bind to the known active sites (Asp214, Glu276 and Asp349). Based on our findings, these (+)-nootkatone derivatives could be used as antidiabetic candidates.