Search

Cordyceps militaris has been long known for valuable health benefits by folk experience and was recently reported with diabetes-tackling evidences, thus deserving extending efforts on screening for component-activity relationship. In this study, experiments were carried out to find the evidence, justification, and input for computations on the potential against diabetes-related protein structures: PDB-4W93, PDB-3W37, and PDB-4A3A. Liquid chromatography identified 14 bioactive compounds in the ethyl acetate extract ( 1 - 14 ) and quantified the contents of cordycepin (0.11%) and adenosine (0.01%). Bioassays revealed the overall potential of the extract against α -amylase (IC 50 = 6.443 ± 0.364 mg.mL -1 ) and α -glucosidase (IC 50 = 2.580 ± 0.194 mg.mL -1 ). A combination of different computational platforms was used to select the most promising candidates for applications as anti-diabetic bio-inhibitors, i.e. 1 (ground state: -888.49715 a.u.; dipole moment 3.779 Debye; DS ¯ -12.3 kcal.mol -1 ; polarizability 34.7 Å 3 ; log P  - 1.30), 10 (ground state: -688.52406 a.u.; dipole moment 5.487 Debye; DS ¯ -12.6 kcal.mol -1 ; polarizability 24.9 Å 3 ; log P  - 3.39), and 12 (ground state: -1460.07276 a.u.; dipole moment 3.976 Debye; DS ¯ -12.5 kcal.mol -1 ; polarizability 52.4 Å 3 ; log P  - 4.39). The results encourage further experimental tests on cordycepin ( 1 ), mannitol ( 10 ), and adenosylribose ( 12 ) to validate their in-practice diabetes-related activities, thus conducive to hypoglycemic applications.Communicated by Ramaswamy H. Sarma.

Diabetes mellitus is considered as one of the principal global health urgencies of the twenty first century. In the present investigation, novel N -substituted 2,4-thiazolidinedione derivatives were designed, synthesized, and characterized by spectral techniques. All the newly synthesized N -substituted 2,4-thiazolidinedione derivatives were tested for in vitro α-glucosidase inhibitory activities and compounds A-12 and A-14 were found to be the most potent which were further subjected to in-vivo disaccharide loading test. The most potent compound was also found to be non-toxic in cytotoxicity studies. Further, docking studies were carried out to investigate the binding mode and key interactions with amino acid residues of α-glucosidase. Molecular dynamic simulations studies for the compounds acarbose, A2, A12, and A14 were done with α-glucosidase protein. Further, ΔG was calculated for acarbose, A2, A12, and A14. In silico studies and absorption, distribution, metabolism, excretion (ADME) prediction studies were also executed to establish the 'druggable' pharmacokinetic profiles. Here, we have developed novel N -substituted TZD analogues with different alkyl groups as α -glucosidase inhibitors.Communicated by Ramaswamy H. Sarma.

Type 2 diabetes accounts for the largest percentage of all diabetic cases worldwide. Cucurbitane-type triterpenes are mainly found in Momordica charantia and possess excellent pharmacological activities. This study was designed to identify cucurbitane-type triterpene from Momordica charantia using Liquid Chromatography-Mass Spectrometry (LC-MS) analysis, examine its anti-diabetic property with molecular docking against diabetes enzymes (alpha-amylase, alpha-glucosidase, dipeptidyl dipeptidase IV and peroxisome proliferator-activated receptor gamma). The stability and interactions of the docked complexes were investigated using molecular dynamics simulation, while the pharmacokinetic and toxicity profile of the ligand was examined using an ADMET server. (23E)-Cucurbita-5,23,25-triene-3,7-dione (CUB) was identified from the LC-MS profiling of the methanolic extract of M. charantia . The molecular docking studies showed that the identified phytochemical elicited good binding energy against all the target receptors. The RMSD and RMSF plots obtained from the 100 ns molecular dynamics simulation showed that the ligand was stable and established substantial interactions with the amino acid residues of the diabetes enzymes which were confirmed by the MM\GBSA computations. The pharmacokinetic and toxicity properties of the ligand showed it was safer as an anti-diabetic drug candidate. Extensive isolation, in vitro and in vivo studies of the ligand against the diabetic enzymes is recommended.Communicated by Ramaswamy H. Sarma.

This study examines the nutritional composition, phytochemical profiling, and antioxidant, antidiabetic, and anti-inflammatory potential of a methanolic extract of Spilanthes filicaulis leaves (MESFL) via in vitro , ex vivo , and in silico studies. In vitro antioxidant, antidiabetic, and anti-inflammatory activities were examined. In the ex vivo study, liver tissues were subjected to FeSO 4 -induced oxidative damage and treated with varying concentrations of MESFL. MESFL contains a reasonable amount of nitrogen-free extract, moisture, ash content, crude protein, and fat, with a lesser amount of crude fiber. According to GC-MS analysis, MESFL contains ten compounds, the most abundant of which are 13-octadecenal and Ar-tumerone. In this study, MESFL demonstrated anti-inflammatory activities via membrane stabilizing properties, proteinase inhibition, and inhibition of protein denaturation (IC 50 = 72.75 ± 11.06 µg/mL). MESFL also strongly inhibited both α-amylase (IC 50 = 307.02 ± 4.25 µg/mL) and α-glucosidase (IC 50 = 215.51 ± 0.47 µg/mL) activities. Our findings also showed that FeSO 4 -induced tissue damage decreased the levels of GSH, SOD, and CAT activities while increasing the levels of MDA. In contrast, treatment with MESFL helped to restore these parameters to near-normal levels, which signifies that MESFL has great potential to address complications from oxidative stress. Furthermore, the in silico interaction of the GCMS-identified phytochemicals with the active sites of α-amylase and α-glucosidase via molecular and ensembled-based docking displayed strong binding affinities of Ar-tumerone and 4-hydroxy-3-methylacetophenone to α-amylase and α-glucosidase, respectively. Taken together, the biological activities of MESFL might be a result of the effects of these secondary metabolites.Communicated by Ramaswamy H. Sarma.

Background: Using an analogue-based drug design approach, a number of novel 2-substituted-1,3-thiazolone derivatives (3-10) have been produced and given permission to proceed for their anti-inflammatory properties. In the present paper, the new thiazole derivatives were designed, synthesized, and tested for their alpha-glucosidase, alpha-amylase, and COX-inhibitory activities. Approving the anti-diabetic activity., Results: All the new derivatives were assessed in vitro compared to control (Acarbose) alpha-glucosidase, and alpha-amylase inhibition influence was showed shown through (3, 5, and 7) that were the most effective compounds as α-glucosidase inhibitors., Conclusions: Compounds (4 and 7) achieved the best effect as α-amylase inhibitors showed by IC 50 score near to that of control (Acarbose). Meanwhile, compound (4) exhibited a lower ferric-reducing anti-oxidant power (FRAP) value when compared to the control experiment (ascorbic acid). A molecular docking study approved the binding affinity and mode of binding of compounds (4 and 5) to the α-glucosidase and α-amylase binding pockets.

Aims: This study focuses on the synthesis and characterization of novel sitagliptin derivatives, aiming to develop potent, orally active anti-diabetic agents with minimal side effects for the management of type 2 diabetes mellitus. Copper (II) (SCu1-SCu9) and zinc (II) (SZn1-SZn9) metal complexes of sitagliptin-based derivatives were synthesized via a template reaction., Material & Method: The synthesized complexes were comprehensively characterized using elemental analysis, FTIR, UV-Vis, 1 h NMR, and 13C NMR spectroscopy. The biological efficacy of these compounds was assessed through α-amylase and α-glucosidase enzyme inhibition assays, with molecular simulation studies providing additional confirmation of their inhibitory activity., Results: Among the tested derivatives, SD7, SD4, SD3, SD5, and SD9 demonstrated enzyme inhibition profiles comparable to the standard inhibitors. However, the metal complexes exhibited absorption challenges, which may influence their bioavailability., Conclusion: These findings highlight the significant anti-diabetic potential of the synthesized compounds against targeted enzymes, establishing a foundation for their development as lead molecules in future therapeutic research.

Inhibition of α-glucosidase and α -amylase are key tactics for managing blood glucose levels. Currently, stronger, and more accessible inhibitors are needed to treat diabetes. Indeno[1,2- b ] quinoxalines-carrying thiazole hybrids 1-17 were created and described using NMR. All analogues were tested for hypoglycaemic effect against STZ-induced diabetes in mice. Compounds 4 , 6 , 8 , and 16 were the most potent among the synthesised analogues. These hybrids were examined for their effects on plasma insulin, urea, creatinine, GSH, MDA, ALT, AST, and total cholesterol. Moreover, these compounds were tested against α -glucosidase and α -amylase enzymes in vitro . The four hybrids 4 , 6 , 8 , and 16 represented moderate to potent activity with IC 50 values 0.982 ± 0.04, to 10.19 ± 0.21 for α -glucosidase inhibition and 17.58 ± 0.74 to 121.6 ± 5.14 μM for α -amylase inhibition when compared to the standard medication acarbose with IC 50 =0.316 ± 0.02 μM for α -glucosidase inhibition and 31.56 ± 1.33 μM for α -amylase inhibition. Docking studies as well as in silico ADMT were done.

Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC 50  = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC 50  = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease mainly caused by insulin resistance, which can lead to a series of complications such as cardiovascular disease, retinopathy, and its typical clinical symptom is hyperglycaemia. Glucosidase inhibitors, including Acarbose, Miglitol, are commonly used in the clinical treatment of hypoglycaemia. In addition, Protein tyrosine phosphatase 1B (PTP1B) is also an important promising target for the treatment of T2DM. Gynostemma pentaphyllum is a well-known oriental traditional medicinal herbal plant, and has many beneficial effects on glucose and lipid metabolism. In the present study, three new and nine known dammarane triterpenoids isolated from G. pentaphyllum , and their structures were elucidated by spectroscopic methods including HR-ESI-MS, 1 H and 13 C NMR and X-ray crystallography. All these compounds were evaluated for inhibitory activity against α-glucosidase, α-amylase and PTP1B. The results suggested that compounds 7 ∼ 10 were potential antidiabetic agents with significantly inhibition activity against PTP1B in a dose-dependent manner.

Aims: Current research work aims to synthesize hybrid compounds with a thiazole-thiazolidinone structure, as potent inhibitors of urease and α-glucosidase enzymes., Materials and Methods: These compounds were characterize through 1 HNMR, 13 CNMR and HREI-MS techniques. These compounds were also evaluated for their potential to inhibit urease and α-glucosidase enzymes for the treatment of urinary tract infections (UTIs) and diabetes treatments. Moreover, molecular docking and ADMET analysis was carried out to confirm biological outcomes., Results and Conclusion: Compounds-4 (IC 50  = 1.80 ± 0.80 and 3.61 ± 0.59 μM against urease and α-glucosidase, respectively) exhibited significant effectiveness in inhibiting the activity of both enzymes in comparison to the conventional inhibitors thiourea and acarbose. Molecular docking experiments showed that potent compounds exhibited favorable binding orientations in the active sites of urease and α-glucosidase playing a pivotal role in inhibition profile of these compounds. These compounds were also investigated for their drug likeness and were found with desirable attributes for pharmaceutical development. Based on the findings of this research, these compounds have the potential to be developed into effective anti-diabetic and anti-urease treatments in the future.

Aim: Quinoline scaffolds are serving as the core structure for numerous antifungal, analgesic, antipyretic, anti-inflammatory drugs as well as have also been investigated for their potential antidiabetic properties. Though further exploration is required in this area as the current antidiabetic agents, such as acarbose, miglitol and voglibose, are associated with several adverse side effects. In this context, arylated tetrahydrobenzo[ H ]quinoline-3-carbonitrile derivatives were designed and evaluated as potential antidiabetic agents. Materials & methods: A one-pot multicomponent reaction of 6-methoxy-1-tetralone with ethyl cyanoacetate, ammonium acetate and varying aldehydes yielded a range of new arylated tetrahydrobenzo[ h ]quinoline-3-carbonitrile molecules 1-36 . Results: Compounds 2-5 , 12 , 13 , 19 and 32-34 showed excellent inhibition against α-amylase (IC 50  = 3.42-15.14 μM) and α-glucosidase (IC 50  = 0.65-9.23 μM) enzymes in comparison to the standard acarbose (IC 50  = 14.35 μM). In addition, all compounds revealed significant to moderate DPPH radical scavenging activity (SC 50  = 21.30-138.30 μM) compared with BHT (SC 50  = 64.40 μM). Kinetic studies confirmed competitive inhibition mode, while molecular docking studies comprehend ligands' interaction with enzyme's active sites and absorption, distribution, metabolism, and excretion analysis confirms that all synthetic derivatives are nontoxic. Conclusion: This research offers a range of lead candidates to become antidiabetic agents after further advanced study.

Diabetes mellitus (DM) is a global pandemic that is characterized by high blood glucose levels. Conventional treatments have limitations, leading to the search for natural alternatives. This study focused on Solanum torvum (STV), a medicinal plant, to identify potential anti-diabetic compounds using molecular docking and molecular dynamics simulations. We focused on identifying natural inhibitors of two key enzymes involved in glucose metabolism: α-amylase (1HNY) and α-glucosidase (4J5T). In our preliminary docking study, rutin showed the highest binding affinity (-11.58 kcal/mol) to α-amylase, followed by chlorogenin (-7.58 kcal/mol) and myricetin (-5.82 kcal/mol). For α-glucosidase, rutin had the highest binding affinity (-11.78 kcal/mol), followed by chlorogenin (-7.11 kcal/mol) and fisetin (-6.44 kcal/mol). Hence, chlorogenin and rutin were selected for further analysis and compared with acarbose, an FDA-approved antidiabetic drug. Comparative docking revealed that chlorogenin had the highest binding affinity of (-9.9 kcal/mol) > rutin (-8.7 kcal/mol) and > acarbose (-7.7 kcal/mol) for α-amylase. While docking with α-glucosidase, chlorogenin again had the highest binding affinity of (-9.8 kcal/mol) > compared to rutin (-9.5 kcal/mol) and acarbose (-7.9 kcal/mol). Molecular dynamics (MD) simulations were conducted to assess their stability. We simulated 100 nanoseconds (ns) trajectories to analyze their stability on various parameters, including RMSD, RMSF, RG, SASA, H-bond analysis, PCA, FEL, and MM-PBSA on the six docked proteins. In conclusion, our study suggests that chlorogenin and rutin derived from STV may be effective natural therapeutic agents for diabetes management because of their strong binding affinities for the α-amylase and α-glucosidase enzymes.Communicated by Ramaswamy H. Sarma.

This research explored novel antidiabetic drugs from natural sources using the Ayurvedic Rasayana herb Ichnocarpus frutescens through invitro enzyme assay, kinetics study, and computational approaches. Invitro enzyme inhibition assay demonstrated the promising inhibitory activity of root extract against alpha-amylase (α-A) and alpha-glucosidase (α-G) enzyme with IC 50 value 7.34 ± 0.22 mg/ml and 4.40 ± 0.25 mg/ml respectively. Enzyme kinetic study revealed the competitive inhibition of both proteins by Ichnocarpus frutescens extract. High-Resolution Liquid Chromatography Mass Spectrometer and Docking study revealed the better binding energy of phytoconstituents 23-Acetoxysoladulcidine, Atrovirinone, Bismurrayaquinone A, Lamprolobine, Zygadenine, and Gambiriin A3 than standard drug acarbose. Molecular modelling showed stable protein-ligands binding interaction during the 100 ns simulation. It revealed comparable Root Mean Square Deviation, Radius of Gyration, and Solvent Accessible Surface Area of these compounds with acarbose. The active site residues of both proteins remained stable and showed significantly less Root Mean Square Fluctuation. Molecular Mechanics with Generalised Bonn Surface Area analysis has illustrated the similar inhibitory activity of Zygadenine for α-A, 23-Acetoxysoladulcidine, and Gambiriin A3 for α-G protein, compared to the FDA-approved drug acarbose. Thus, the study suggested that the root of Ichnocarpus frutescens can be used as α-A and α-G inhibitors and be considered a compelling lead for the medication of type 2 diabetes.Communicated by Ramaswamy H. Sarma.

Aim: The purpose of this study is to design and synthesize a series of novel chalcone amide α-glucosidase (AG) inhibitors ( L1-L10 ) based on virtual screening and molecular dynamics (MD) simulation. Materials & methods: Target compounds ( L1-L10 ) were synthesized from 2-hydroxyacetophenone and methyl 4-formylbenzoate. Results: In vitro activity test shows that most compounds have good AG inhibition. Specially, compound L4 (IC 50  = 8.28 ± 0.04 μM) had the best inhibitory activity, superior to positive control acarbose (IC 50  = 8.36 ± 0.02 μM). Molecular docking results show that the good potency of L4 maybe attributed to strong interactions between chalcone skeleton and active site, and the torsion of carbon nitrogen bond in amide group. Conclusion: Compound L4 maybe regard as a good anti-Type II diabetes candidate to preform further study.

Diabetes is a common lifestyle disorder found in populations of different age groups. Maltase-glucoamylase catalyses the release of the glucose molecule in the final enzymatic reaction of starch digestion; therefore, inhibition of maltase-glucoamylase is one of the approaches in the development of therapeutics for diabetes. Citrullus colocynthis is commonly recommended in Ayurveda for the treatment of diabetes. The current study applied a structure-based drug design approach to repurpose the phytochemicals of Citrullus colocynthis to identify potential inhibitors for maltase-glucoamylase. 70 phytochemicals of Citrullus colocynthis were screened against maltase-glucoamylase and top 5 molecules 8-p-hydroxybenzylisovitexin, isoorientin, cucurbitacin B, cucurbitacin E, and cucurbitacin I with significant binding energy of -10 kcal/mol, -9.9 kcal/mol, -9.6 kcal/mol, -9.2 kcal/mol, and -7.7 kcal/mol were identified. Furthermore, MMGBSA, pharmacokinetics properties and toxicity prediction were performed on the five identified molecules and top 3 molecules were selected for molecular dynamics (MD) simulation. It was observed from the structural flexibility and dynamic behaviour of the systems that conformational changes were noticed in the complexes as compared to its native state, which suggests that the 3 molecules, namely 8-p-hydroxybenzylisovitexin, isoorientin, and cucurbitacin I of Citrullus colocynthis may act as inhibitors for maltase-glucoamylase.Communicated by Ramaswamy H. Sarma.

Phytochemicals are now increasingly exploited as remedial agents for the management of diabetes due to side effects attributable to commercial antidiabetic agents. This study investigated the structural and molecular mechanisms by which betulinic acid exhibits its antidiabetic effect via in vitro and computational techniques. In vitro antidiabetic potential was analysed via on α -amylase, α -glucosidase, pancreatic lipase and α -chymotrypsin inhibitory assays. Its structural and molecular inhibitory mechanisms were investigated using Density Functional Theory (DFT) analysis, molecular docking and molecular dynamics (MD) simulation. Betulinic acid significantly ( p  < 0.05) inhibited α -amylase, α -glucosidase, pancreatic lipase and α -chymotrypsin enzymes with IC 50 of 70.02 μg/mL, 0.27 μg/mL, 1.70 μg/mL and 8.44 μg/mL, respectively. According to DFT studies, betulinic acid possesses similar reaction in gaseous phase and water due to close values observed for highest occupied molecular orbital (HOMO) and lowest occupied molecular orbital (LUMO) and the chemical descriptors. The dipole moment indicates that betulinic acid has high polarity. Molecular electrostatic potential surface revealed the electrophilic and nucleophilic attack-prone atoms of the molecule. Molecular dynamic studies revealed a stable complex between betulinic acid and α-amylase, α-glucosidase, pancreatic lipase and α-chymotrypsin. The study elucidated the potent antidiabetic properties of betulinic acid by revealing its conformational inhibitory mode of action on enzymes involved in the onset of diabetes.

Alpinia officinarum is a commonly used spice with proven folk uses in various traditional medicines. In the current study, six compounds were isolated from its rhizomes, compounds 1-3 were identified as diarylheptanoids, while 4-6 were identified as flavonoids and phenolic acids. The isolated compounds were subjected to virtual screening against α-glucosidase, butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) enzymes to evaluate their potential antidiabetic and anti-Alzheimer's activities. Molecular docking and dynamics studies revealed that 3 exhibited a strong binding affinity to human a α- glucosidase crystal structure compared to acarbose. Furthermore, 2 and 5 demonstrated high potency against AChE. The virtual screening results were further supported by in vitro assays, which assessed the compounds' effects on α-glucosidase, cholinesterases, and their antioxidant activities. 5-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-phenylheptan-3-one (2) showed potent antioxidant effect in both ABTs and ORAC assays, while p -hydroxy cinnamic acid (6) was the most potent in the ORAC assay. In contrary, kaempferide (4) and galangin (5) showed the most potent effect in metal chelation assay. 5-Hydroxy-1,7-diphenylhepta-4,6-dien-3-one (3) and 6 revealed the most potent effect as α-glucosidase inhibitors where compound 3 showed more potent effect compared to acarbose. Galangin (5) revealed a higher selectivity to BChE, while 2 showed the most potent activity to (AChE).

High blood sugar is a defining feature of chronic disease, diabetes mellitus (DM). There are numerous commercially available medications for the treatment of DM. However, managing the patient's glucose levels remain a challenge because of the gradual reduction in beta-cell function and some side effects from the long-term use of various medications. Previous research has shown that the phenolic compound of henna plant ( Lawsonia inermis L.) has the potential as anti-diabetic agent since it is able to suppress the digesting of α-amylase enzyme. In these studies, the plant' phenolic compounds have been isolated and characterized using UV, IR, NMR and LC-MS methods. Furthermore, the compound interaction into the active site of the α-amylase enzyme has been analyzed using molecular docking and molecular dynamics, as well as into α-glucosidase enzyme for predicting of the affinities. The results showed that isolated compound has the molecular formula of C 15 H 10 O 6 with eleven degrees of unsaturation (DBE; double bond equivalence). The DBE value corresponds to the structure of the luteolin compound having an aromatic ring (8), a carbonyl group on the side chain (1) and a ketone ring with (2). The interaction study of the isolated compound with α-amylase and α-glucosidase enzyme using molecular docking compared to the positive control (acarbose) gave binding energy of -8.03 and -8.95 kcal/mol, respectively. The molecular dynamics simulation using the MM-PBSA method, complex stability based on solvent accessible surface area (SASA), root mean square deviation (RMSD), and root mean square fluctuation (RMSF) revealed that the compound has a high affinity for receptors. The characteristics of skin permeability, absorption, and distribution using ADME-Tox model were also well predicted. The results indicate that the phenolic compound isolated from L. inermis leaf was luteolin and it has the potential as an anti-diabetic agent.Communicated by Ramaswamy H. Sarma.

Background: Diabetes is characterized by a lack of insulin and insensitivity to insulin. In 2013, the global diabetes population was 382 million, with 90% of them having type 2 diabetes (non-insulin-dependent). It is predicted that this number will increase to 592 million by 2035. Aim: Here, we aimed to synthesize a series of benzimidazole-based derivatives B1 - B32 with α-glucosidase inhibition potential as antidiabetic agents. Methods: Compounds B1 - B32 were prepared in three three-step reactions, and the structures were elucidated using spectroscopic methods, namely 1H NMR, 13C NMR, MS and IR. Enzyme inhibition and kinetic study were done using commercial assay kits, and molecular docking study using autodock4. Results: Bioassay data showed that twenty-four out of the thirty-two tested compounds exhibited IC50 values ranging from 44 to 745 μM, surpassing the standard molecule, acarbose (IC50: 750 μM). it was determined that the best compound, B10 , functions as a competitive inhibitor. Additionally, a molecular docking study provided insights into the interactions between the four most promising compounds ( B5 , B6 , B10 and B28 ) and the active site residues within the enzyme. Conclusion: The tested compounds are interesting α-glucosidase inhibitors, which indicates the benefit of more bioassay studies, especially in vivo studies.

This research is carried out to explore the hypoglycemic activity of Syzygium cumini seed extracts by in vitro , in vivo , and in silico methods. For in vitro studies the α-amylase and α-glucosidase enzyme inhibition assays were employed. For in vivo studies 30 alloxan induced Wistar rats were used. They were orally administered with glibenclamide and low/high dose of the extracts and were monitored regularly for the change in blood glucose levels for about 28 days. The in silico molecular docking was conducted to evaluate the binding interaction of 1,2,3-Benzenetriol with human pancreatic α-amylase and α-glucosidase. It was found that all the extracts were able to inhibit the α-amylase and α-glucosidase enzymes. Among which the acetone extract showed greater inhibition with 72.52 ± 0.51% and 63.02 ± 0.73% for both the enzymes, respectively. There was significant ( p  < 0.05) reduction in blood glucose levels in the rats administered with glibenclamide and extracts. In silico docking results revealed that the compound 1,2,3-Benzenetriol exhibited the highest binding affinity for human pancreatic α-amylase with binding energy -7.7 kcal/mol. Thus suggesting the utilization of S. cumini seeds in the management of diabetes mellitus.Communicated by Ramaswamy H. Sarma.

In this work, we developed a series of novel 5-[3-(4-chlorophenyl)-substituted-1,3-dimethylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione derivatives 4(a-e) via a one-pot multicomponent reaction. The structures of the compounds were confirmed using analytical and spectroscopic techniques. Also, the synthesized compounds were screened for their anti-diabetic activity, cytotoxicity and in silico studies. The activity results suggested that the compound 4e exhibited least IC 50 values of 0.055 ± 0.002 µM, 0.050 ± 0.002 µM and 0.009 ± 0.001 µM for α-amylase, α-glucosidase and cytotoxicity respectively. Further, in silico molecular docking results revealed that all the obtained compounds effectively interacted with exo-β-D-glucosaminidase and P38 MAP kinase proteins with good binding energies. In that, 4e compound established the least binding energy of -9.6 and -9.1 kcal/mol, respectively. Moreover, our synthesized compounds were subjected to ADME studies, which suggested that all the synthesized compounds obeyed all five rules with good bioavailability and were suitable as drug leads against anti-diabetic and anticancer treatment.

Aim: The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. Materials & methods: 20 new benzothiazole-appended indenopyrazoles, 3a-t , were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Results: Among all the hydroxypyrazolones, 3p and 3r showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Conclusion: Compounds 3p and 3r have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.

Background: Derivatization has been tremendously utilized in the field of drug discovery for optimizing the pharmacological properties and improving safety, efficacy and selectivity. Methodology: Schiff's bases (AD1-AD11) are synthesized through amantadine condensation with different aldehydes and ketones. Fourier transform infrared, 1 H NMR, 13 C NMR, TLC, liquid chromatography mass spectrometry analysis, in silico studies, molecular docking and antiviral activity through hemagglutinin test were performed for evaluation of new compounds. Results: AD2, 3 and 9-11 showed greater antiviral activity than the parent drug. Among all derivatives, AD2 and AD3 exhibited good potential against α-amylase while AD7 and AD10 showed stronger inhibition against α-glucosidase. Conclusion: So, it is concluded that the most potent derivatives can be used as lead compounds in novel drug design of antiviral antidiabetic agents.

Aim: The goal of this study is to synthesize new metal complexes containing N -methyl-1-(pyridin-2-yl)methanimine and azide ligands as α-glucosidase inhibitors for Type 2 diabetes. Materials & methods: The target complexes ( 12-16 ) were synthesized by reacting N -methyl-1-(pyridin-2-yl)methanimine (L 1 ) with sodium azide in the presence of corresponding metal salts. The investigation of target protein interactions, vibrational, electronic and nonlinear optical properties for these complexes was performed by molecular docking and density functional theory studies. Results: Among these complexes, complex 13 (IC 50  = 0.2802 ± 0.62 μM) containing Hg ion showed the highest α-glucosidase inhibitory property. On the other hand, significant results were detected for complexes containing Cu and Ag ions. Conclusion: Complex 13 may be an alternate anti-diabetic inhibitor according to in vitro /docking results.

Type 2 diabetes (T2D) is a progressive metabolic disorder of glucose metabolism. One of the therapeutic approaches for the treatment of T2D is reducing postprandial hyperglycaemia through inhibition of the digestive enzymes α-glucosidase and α-amylase. In this context, aimed at identifying natural products endowed with anti-T2D potential, we focused on Ptilostemon casabonae (L.) Greuter, a species belonging to Asteraceae family. Enzymatic inhibition, antioxidant activity, phenolic composition and cellular assays were performed. This study revealed that the P. casabonae hydroalcoholic extract exerts a potent inhibitory activity against α-glucosidase. This activity is supported by an antioxidant effect, preventing ROS formation in a stressed cellular system. HPLC-PDA-MS/MS analysis, revealed a complex polyphenolic fraction. Among the tested pure compounds, 1,5-dicaffeoylquinic acid, apigenin and rutin displayed good α-glucosidase inhibitory activity. Our study suggested new potential of P. casabonae encouraging us to further testing the possible therapeutic potential of this extract.

Lavandula angustifolia Mill. (lavender) is one of the most used medicinal plants. Herein, we chemically characterised and investigated the antioxidant properties and the capability to inhibit key enzymes for the treatment of type 2 diabetes (TD2) and obesity such as pancreatic lipase, α-glucosidase, and α-amylase of the ethanolic extract of two lavender samples (La1 and La2) from southern Italy. Both extracts significantly inhibited α-glucosidase, while La1 inhibited α-amylase and lipase more effectively than La2. To investigate whether these properties could be due to a direct interaction of the main constituents of the extracts with the targeted enzymes, molecular docking studies have been performed. As a result, the selected compounds were able to interact with the key residues of the binding site of the three proteins, thus supporting biological data. Current findings indicate the new potential of lavender ethanolic extract for the development of novel agents for T2D and obesity.

Context: Lysiphyllum strychnifolium (Craib) A. Schmitz (LS) (Fabaceae) has traditionally been used to treat diabetes mellitus., Objective: This study demonstrates the antidiabetic and antioxidant effects of aqueous extract of LS leaves in vivo and in vitro ., Materials and Methods: The effects of aqueous LS leaf extract on glucose uptake, sodium-dependent glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) mRNA expression in Caco-2 cells, α-glucosidase, and lipid peroxidation were evaluated in vitro . The antidiabetic effects were evaluated using an oral glucose tolerance test (OGTT) and a 28-day consecutive administration to streptozotocin (STZ)-nicotinamide (NA)-induced type 2 diabetic mice., Results: The extract significantly inhibited glucose uptake (IC 50 : 236.2 ± 36.05 µg/mL) and downregulated SGLT1 and GLUT2 mRNA expression by approximately 90% in Caco-2 cells. Furthermore, it non-competitively inhibited α-glucosidase in a concentration-dependent manner with the IC 50 and K i of 6.52 ± 0.42 and 1.32 µg/mL, respectively. The extract at 1000 mg/kg significantly reduced fasting blood glucose levels in both the OGTT and 28-day consecutive administration models as compared with untreated STZ-NA-induced diabetic mice ( p  < 0.05). Significant improvements of serum insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and GLUT4 levels were observed. Furthermore, the extract markedly decreased oxidative stress markers by 37-53% reduction of superoxide dismutase 1 (SOD1) in muscle and malondialdehyde (MDA) in muscle and pancreas, which correlated with the reduction of MDA production in vitro (IC 50 : 24.80 ± 7.24 µg/mL)., Conclusion: The LS extract has potent antihyperglycemic activity to be used as alternative medicine to treat diabetes mellitus.

Background: Medication used to treat Type 2 diabetes by decreasing the absorption of carbohydrates in the intestine consists of α-glucosidase inhibitors. Polyhydroquinoline derivatives have attracted interest as excellent antidiabetic agents. Methods: Polyhydroquinoline derivatives ( 1-17 ) were synthesized and tested for in vitro α-glucosidase inhibitory activity. Results: All the synthesized compounds exhibited excellent to good inhibitory activity, having IC 50 values from 1.23 ± 0.03 to 73.85 ± 0.61 μM, compared with the standard drug, acarbose. The binding mechanism of these derivatives with α-glucosidase was deduced by docking studies and indicated that a slight variation in the orientation of compounds, affects their binding capability. Conclusion: In order to find new antidiabetic drugs, this study has discovered prospective lead candidates.

In this exploration, we assessed the antihyperglycaemic properties of methanol extract of flowers of Thunbergia mysorensis (MeT) against α-glucosidase, α-amylase and aldose reductase enzymes for the effective management of postprandial hyperglycemia. Hyperglycemia occurs when the body lacks enough insulin or is unable to correctly utilize it. MeT inhibited both the carbohydrate digestive enzymes (α-glucosidase and α-amylase) and aldose reductase, which are vital for the therapeutic control of postprandial hyperglycaemia. MeT was also found to have significant antioxidant activity. Using several spectroscopic approaches, the primary active component found in MeT was identified as gallic acid. With low Ki values, gallic acid significantly inhibited α-glucosidase (30.86 µg/mL) and α-amylase (6.50 µg/mL). Also, MeT and gallic acid both inhibited aldose reductase effectively, corresponding to an IC 50 value of 3.31 and 3.05 µg/mL. Our findings imply that the presence of polyphenol compounds (identified via HPLC analysis) is more likely to be responsible for the antihyperglycaemic role exhibited by MeT via the inhibition of α-glucosidase and the polyol pathway. Further, gallic acid interacted with the key residues of the active sites of α-glucosidase (-6.4 kcal/mol), α-amylase (-5.8 kcal/mol) and aldose reductase (-5.8 kcal/mol) as observed in the protein-ligand docking. It was also predicted that gallic acid was stable inside the binding pockets of the target enzymes during molecular dynamics simulation. Overall, gallic acid derived from MeT via bioassay-guided isolation emerges as a natural antidiabetic drug and can be taken into in vivo and clinical studies shortly.Communicated by Ramaswamy H. Sarma.

Aims: The current study aimed to develop new thiourea derivatives as potential α-glucosidase inhibitors for the management of hyperglycemia in patients of Type 2 diabetes, with a focus on identifying safer and more effective antidiabetic agents. Materials & methods: New thiourea derivatives ( 1-16 ) were synthesized through single-step chemical transformation and evaluated for in vitro α-glucosidase inhibition. Kinetic studies identified the mode of inhibition, free energy and type of interactions were analyzed through density functional theory and molecular docking. Results & conclusion: Compound 5 was identified as the most potent, noncompetitive and noncytotoxic inhibitor of α-glucosidase enzyme with a half-maximal inhibitory concentration of 24.62 ± 0.94 μM. Computational studies reinforce experimental results, demonstrating significant enzyme interactions via hydrophobic and π-π stacking forces.

Background: Diabetes mellitus (DM) is a chronic disorder, considered to be a major global health challenge in the 21st century. α-Glucosidase enzyme is a well-known drug target to treat Type II DM. Methods: A new library of biphenyl-substituted triazines was synthesized and confirmed by various spectroscopic techniques. Results: All compounds showed potent α -glucosidase inhibitory activity, with IC 50 values ranging from 35.35 ± 0.34 to 564.41 ± 0.91 μM, as the standard acarbose, IC 50 value of 750.7 ± 0.13 μM. Our in silico study has predicted key interactions with the enzyme's active site. Drug-likeness and absorption, distribution, metabolism, excretion and toxicity were also studied. Conclusion: This study has identified a range of potential hits against the α-glucosidase enzyme that may serve as antidiabetic agents after further investigations.

Background: Researchers seeking new drug candidates to treat diabetes mellitus have been exploring bioactive molecules found in nature, particularly tetrahydropyridines (THPs). Methods: A library of THPs ( 1-31 ) were synthesized via a one-pot multicomponent reaction and investigated for their inhibition potential against α-glucosidase and α-amylase enzymes. Results: A nitrophenyl-substituted compound 5 with IC 50 values of 0.15 ± 0.01 and 1.10 ± 0.04 μM, and a K m value of 1.30 mg/ml was identified as the most significant α-glucosidase and α-amylase inhibitor, respectively. Kinetic studies revealed the competitive mode of inhibition, and docking studies revealed that compound 5 binds to the enzyme by establishing hydrophobic and hydrophilic interactions and a salt bridge interaction with His279. Conclusion: These molecules may be a potential drug candidate for diabetes in the future.

Aim: To synthesize pyrrolopyridine-based thiazolotriazoles as a novel class of α-amylase and α-glucosidase inhibitors and to determine their enzymatic kinetics. Methodology: Pyrrolopyridine-based thiazolotriazole analogs ( 1-24 ) were synthesized and characterized through proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance and high-resolution electron ionization mass spectrometry. Results: All synthesized analogs displayed good inhibitory potential of α-amylase and α-glucosidase ranging 17.65-70.7 μM and 18.15-71.97 μM, respectively, compared with the reference drug, acarbose (11.98 μM and 12.79 μM). Analog 3 was the most potent among the synthesized analogs, having α-amylase and α-glucosidase inhibitory activity at 17.65 and 18.15 μM, respectively. The structure-activity relationship and binding modes of interactions between selected analogs were confirmed via docking and enzymatic kinetics studies. The compounds ( 1-24 ) were tested for cytotoxicity against the 3T3 mouse fibroblast cell line and were observed to be nontoxic.

Aim: α-Glucosidase inhibitors are important oral antidiabetic drugs that are used alone or in combination therapy. Materials & methods: In this regard, 1,3,4-thiadiazoles-1,2,3-triazoles were designed, synthesized and evaluated for α-glucosidase enzyme inhibition. Results: The applied synthesis protocol involved a 'click' reaction between a novel alkyne derived from a 1,3,4-thiadiazole derivative and phenylacetamide azides. The hybrid ( 9n ) bearing 2-methyl and 4-nitro substituents was the best inhibitor with an IC 50 value of 31.91 μM (acarbose IC 50  = 844.81 μM). The blind molecular docking study of the best derivative ( 9n ) showed that it interacted with the allosteric site's amino acid residues of α-glucosidase. Conclusion: 'Click'-inspired potential α-glucosidase inhibitors (1,3,4-thiadiazole-1,2,3-triazole hybrids) were identified and structure-activity relationship and kinetic and molecular docking studies accomplished.

Lawsonia inermis (henna) has been used in traditional medicine throughout the world and biological property of its flower has been least explored. In the present study, the phytochemical characterization and biological activity ( in vitro radical scavenging activity, anti-alpha glucosidase and anti-acetylcholinesterase) of aqueous extract prepared from henna flower (HFAE) was carried out by both Qualitative and quantitative phytochemical analysis and Fourier-transform infrared spectroscopy revealed the functional group of the phytoconstituents such as phenolics, flavonoids, saponin, tannins and glycosides. The phytochemicals present in HFAE was preliminary identified by liquid chromatography/electrospray ionization tandem mass spectrometry. The HFAE showed potent in vitro antioxidant activity and the HFAE inhibited mammalian α-glucosidase (IC 50 = 129.1 ± 5.3 µg/ml; Ki = 38.92 µg/ml) and acetylcholinesterase (AChE; IC 50 = 137.77 ± 3.5 µg/ml; Ki = 35.71 µg/ml) activity by competitive manner. In silico molecular docking analysis revealed the interaction of active constituents identified in HFAE with human α-glucosidase and AChE. Molecular dynamics simulation for 100 ns showed the stable binding of top two ligand/enzyme complexes with lowest binding energy such as 1,2,3,6-Tetrakis-O-galloyl-beta-D-glucose (TGBG)/human α-glucosidase, Kaempferol 3-glucoside-7-rhamnoside (KGR)/α-glucosidase, agrimonolide 6-O-β-D-glucopyranoside (AMLG)/human AChE and KGR/AChE. Through MM/GBSA analysis, the binding energy for TGBG/human α-glucosidase, KGR/α-glucosidase, AMLG/human AChE and KGR/AChE was found to be -46.3216, -28.5772, -45.0077 and -47.0956 kcal/mol, respectively. Altogether, HFAE showed an excellent antioxidant, anti-alpha glucosidase and anti-AChE activity under in vitro . This study suggest HFAE with remarkable biological activities could be further explored for therapeutics against type 2 diabetes and diabetes-associated cognitive decline.Communicated by Ramaswamy H. Sarma.

Diabetes is one of the most common metabolic diseases in humans and the use of herbal medicines is of great clinical importance to inhibit carbohydrate-hydrolyzing enzymes and reduce blood glucose levels in diabetic patients. Inhibition of glycosidase activity is an effective way to treat and prevent diabetes. Therefore, in this study, curcumin-based benzaldehyde derivatives were synthesized and used as influential agents in the treatment of diabetes with inhibitory properties against two carbohydrate-hydrolyzing enzymes α-glucosidase (α-Glu) and α-amylase (α-Amy) as significant therapeutic targets for reducing postprandial hyperglycemia. Overall, the findings showed that due to the specific inhibitory activity against α-Glu in comparison with α-Amy, as well as more stability and antioxidant activity than curcumin, C5 and C8 derivatives are potentially important anti-diabetic drugs, not only to decrease glycemic index but also to limit the activity of the main production pathways of reactive oxygen species (ROS) in diabetic patients.Communicated by Ramaswamy H. Sarma.

Diabetes is a group of metabolic diseases characterised by chronic hyperglycaemia caused by multiple causes, which is caused by insulin secretion and/or utilisation defects. It is characterised by increased fasting and postprandial blood glucose levels due to insulin deficiency or insulin resistance. It is reported that the harm of diabetes mainly comes from its complications, and the cardiovascular disease caused by diabetes is the primary cause of its harm. China has the largest number of diabetic patients in the world, and the prevention and control of diabetes are facing great challenges. In recent years, many kinds of literature have been published abroad, which have proved that coumarin and its derivatives are effective in the treatment of diabetic complications such as nephropathy and cardiovascular disease. In this paper, the types of antidiabetic drugs and the anti-diabetic mechanism of coumarins were reviewed.

Aiming at finding natural sources of antidiabetics agents, 15 extracts from Brazilian medicinal plants of the Atlantic Forest and Amazon region were tested against α-glucosidase enzyme. Plants were selected based on the taxonomic relationships with genera including several species with antidiabetic activity. In this screening, the extracts obtained from the flowers of Hyptis monticola and the leaves of Lantana trifolia and Lippia origanoides resulted endowed with promising anti-α-glucosidase activity. The extracts from H. monticola and from L. origanoides collected in two different areas, were characterised by ultra-high performance liquid chromatography coupled to mass spectrometry. Bioassay-guided fractionation led to the identification of several enzyme inhibiting compounds, among them the mechanism of action of naringenin and pinocembrin was investigated. The two L. origanoides extracts showed differences in bioactivity and in the phytochemical profiles. The fractionation of the extract from H. monticola led to a partial loss of the inhibitory effect.

Different oleanolic acid (OA) oxime ester derivatives ( 3a - 3t ) were designed and synthesised to develop inhibitors against α -glucosidase and α -amylase. All the synthesised OA derivatives were evaluated against α -glucosidase and α -amylase in vitro. Among them, compound 3a showed the highest α -glucosidase inhibition with an IC 50 of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α -amylase inhibitory with an IC 50 of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α -glucosidase and α -amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells.HighlightsOleanolic acid oxime ester derivatives ( 3a-3t ) were synthesised and screened against α-glucosidase and α-amylase.Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM.Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 µM.Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.

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: 1 H-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.

High-quality semen with high viability is critical to improving the in-vitro fertilization efficiency. This study aimed to understand the effect of ambient temperature and humidity on semen quality and seminal plasma biochemical parameters of Mediterranean buffalo in March and July. The metabolites of seminal plasma in two seasons were detected using the UPLC-MS/MS method. The results showed that temperature and humidity index (THI) in March were 66.86 ± 2.98, and 82.94 ± 3.52 in July. Compared with in March, breath frequency, rectal temperature, and heat shock protein 70 expressions of seminal plasma were significantly increased in July ( p <  0.05), motility of sperm was dramatically reduced, and sperm deformity rate was significantly increased ( p <  0.05). Fructose, acid phosphatase and α-glucosidase in seminal plasma were significantly increased ( p <  0.05) in July, while testosterone level was significantly reduced ( p <  0.05). Six different metabolites were found in the two groups, which involved in three metabolic pathways, the tricarboxylic acid cycle, glycerophospholipid, glyoxylic acid and dicarboxylic acid. The above results indicate that the increased ambient temperature has obvious side effects on the semen quality of Mediterranean buffalo, and the compromised quality is associated with the change of metabolites related to male hormone secretion, energy metabolism and fatty acid oxidation.

Type 2 diabetes mellitus (T2DM) is characterized by elevated blood glucose levels and can lead to serious complications such as nephropathy, neuropathy, retinopathy and cardiovascular disease. The aim of this work is to identify and investigate the inhibition mechanism of natural flavonoids and phenolics acids against, the α-amylase (αA) and α-glucosidase (αG). Therefore, we used different approaches; such as conceptual DFT and pharmacophore mapping in addition to molecular mechanics, dynamics and docking simulations. Whereas, a close agreement was found out to decide that Linarin (Flavones) provides more optimized inhibition of αA and αG enzymes. Our results have shown that Linarin could be useful as preventative agent, and possibly therapeutic modality for the treatment of metabolic diseases.Communicated by Ramaswamy H. Sarma.

Introduction: Pompe disease is an autosomal recessive disorder caused by a deficiency of acid-α-glucosidase (GAA), an enzyme responsible for hydrolyzing lysosomal glycogen. A lack of GAA leads to accumulation of glycogen in the lysosomes of cardiac, skeletal, and smooth muscle cells, as well as in the central and peripheral nervous system. Enzyme replacement therapy has been the standard of care for 15 years and slows disease progression, particularly in the heart, and improves survival. However, there are limitations of ERT success, which gene therapy can overcome., Areas Covered: Gene therapy offers several advantages including prolonged and consistent GAA expression and correction of skeletal muscle as well as the critical CNS pathology. We provide a systematic review of the preclinical and clinical outcomes of adeno-associated viral mediated gene therapy and alternative gene therapy strategies, highlighting what has been successful., Expert Opinion: Although the preclinical and clinical studies so far have been promising, barriers exist that need to be addressed in gene therapy for Pompe disease. New strategies including novel capsids for better targeting, optimized DNA vectors, and adjuctive therapies will allow for a lower dose, and ameliorate the immune response.

A series of N -(alkyl/aryl)-2-chloro-4-nitro-5-[(4-nitrophenyl)sulfamoyl]benzamide derivatives were synthesized and evaluated for its in vitro antidiabetic potential against α-glucosidase and α-amylase enzymes and also for its antimicrobial potential. Compounds N -(2-methyl-4-nitrophenyl)-2-chloro-4-nitro-5-[(4-nitrophenyl)sulfamoyl]benzamide and N -(2-methyl-5-nitrophenyl)-2-chloro-4-nitro-5-[(4-nitrophenyl)sulfamoyl]benzamide were found to be the most potent α-glucosidase and α-amylase inhibitors with IC 50 values of 10.13 and 1.52 µM, respectively. The docking results depicted reasonable dock score -10.2 to -8.0 kcal/mol (α-glucosidase), -11.1 to -8.3 kcal/mol (α-amylase) and binding interactions of synthesized molecules with respective targets with enzymes. During molecular dynamic simulations, analysis of RMSD of ligand protein complex suggested stability of the most active compound at binding site of target proteins. Compound N -(2-chloro-4-nitrophenyl)-2-chloro-4-nitro-5-[(4-nitrophenyl)sulfamoyl] benzamide showed antibacterial potential against Gram positive and Gram negative bacteria and compound N -(2-methyl-5-nitrophenyl)-2-chloro-4-nitro-5-[(4-nitrophenyl)sulfamoyl] benzamide showed excellent antifungal potential against Candida albicans and Aspergillus niger . The computational studies were also executed to predict the drug-likeness and ADMET properties of the title compounds. The N -(alkyl/aryl)-2-chloro-4-nitro-5-[(4-nitrophenyl)sulfamoyl]benzamide derivatives showed significant antidiabetic and antimicrobial potential which is equally supported by the molecular dynamic and docking studies. This study will prove useful in revealing the molecular structure and receptor target site details which can be further utilized for the development of newer active antidiabetic and antimicrobial agents.

The underlying cause of many metabolic diseases is abnormal changes in enzyme activity in metabolism. Inhibition of metabolic enzymes such as cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and α-glucosidase (α-GLY) is one of the accepted approaches in the treatment of Alzheimer's disease (AD) and diabetes mellitus (DM). Here we reported an investigation of a new series of novel ureido-substituted derivatives with sulfamethazine backbone ( 2a-f ) for the inhibition of AChE, BChE, and α-GLY. All the derivatives demonstrated activity in nanomolar levels as AChE, BChE, and α-GLY inhibitors with K I values in the range of 56.07-204.95 nM, 38.05-147.04 nM, and 12.80-79.22 nM, respectively. Among the many strong N -(4,6-dimethylpyrimidin-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives ( 2a-f ) detected against ChEs, compound 2c , the 4-fluorophenylureido derivative, demonstrated the most potent inhibition profile towards AChE and BChE. A comprehensive ligand/receptor interaction prediction was performed in silico for the three metabolic enzymes providing molecular docking investigation using Glide XP, MM-GBSA, and ADME-Tox modules. The present research reinforces the rationale behind utilizing inhibitors with sulfamethazine backbone as innovative anticholinergic and antidiabetic agents with a new mechanism of action, submitting propositions for the rational design and synthesis of novel strong inhibitors targeting ChEs and α-GLY.Communicated by Ramaswamy H. Sarma.

In this study, the rhizome of Cyperus rotundus L was investigated for its antioxidant and antidiabetic effects using in vitro and in silico experimental models. Its crude extracts (ethyl acetate, ethanol and aqueous) were screened in vitro for their antioxidant activity using ferric-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl (DPPH), as well as their inhibitory effect on α-glucosidase enzyme. Subsequently, the extracts were subjected to Gas Chromatography-Mass Spectrometry (GC-MS) analysis to elucidate their possible bioactive compounds. Furthermore, computational molecular docking of selected phenolic compounds was conducted to determine their mode of α-glucosidase inhibitory activity. The aqueous extract displayed the highest level of total phenolic content and significantly higher scavenging activity in both FRAP and DPPH assays compared to ethyl acetate and ethanol extracts. In FRAP and DPPH assays, IC 50 values of aqueous extract were 448.626 µg/mL and 418.74 µg/mL, respectively. Aqueous extract further presented higher α-glucosidase inhibitory activity with an IC 50 value of 383.75 µg/mL. GC-MS analysis revealed the presence of the following phenolic compounds: 4-methyl-2-(2,4,4-trimethylpentan-2-yl) phenol, Phenol,2-methyl-4-(1,1,3,3-tetramethylbutyl)- and 1-ethoxy-2-isopropylbenzene. Molecular docking study revealed 1-ethoxy-2-isopropylbenzene formed two hydrogen bonds with the interacting residues in the active site of α-glucosidase enzyme. Furthermore, 4-methyl-2-(2,4,4-trimethylpentan-2-yl) phenol had the lowest binding energy inferring the best affinity for α-glucosidase active site. These results suggest the possible antioxidant and antidiabetic potential of Cyperus rotundus .Communicated by Ramaswamy H. Sarma.

In the present study, a series of azo derivatives ( TR-1 to TR-9 ) have been synthesised via the diazo-coupling approach between substituted aromatic amines with phenol or naphthol derivatives. The compounds were evaluated for their therapeutic applications against alpha-glucosidase (anti-diabetic) and pathogenic bacterial strains E. coli (gram-negative), S. aureus (gram-positive), S. aureus (gram-positive) drug-resistant strain, P. aeruginosa (gram-negative), P. aeruginosa (gram-negative) drug-resistant strain and P. vulgaris (gram-negative). The IC 50 (µg/mL) of TR-1 was found to be most effective (15.70 ± 1.3 µg/mL) compared to the reference drug acarbose (21.59 ± 1.5 µg/mL), hence, it was further selected for the kinetic studies in order to illustrate the mechanism of inhibition. The enzyme inhibitory kinetics and mode of binding for the most active inhibitor ( TR-1 ) was performed which showed that the compound is a non-competitive inhibitor and effectively inhibits the target enzyme by binding to its binuclear active site reversibly.

The inhibition of α-glucosidase and DPP enzymes capable of effectively reducing blood glucose level in the management of type 2 diabetes. The purpose of the present study is to evaluate the inhibitory potential of α-glucosidase and DPP (IV) activity including with the 2- NBDG uptake assay and insulin secretion activities through in vitro studies. The selected of active compounds obtained from the screening of compounds by LC-MS were docked with the targeted enzyme that involved in the mechanism of T2DM. From the results, root extracts displayed a better promising outcome in α-glucosidase (IC 50 2.72 ± 0.32) as compared with the fruit extracts (IC 50 3.87 ± 0.32). Besides, root extracts also displayed a better activity in the inhibition of DPP (IV), enhance insulin secretion and glucose uptake activity. Molecular docking results revealing that phlorizin binds strongly with α-glucosidase, DPP (IV) and Insulin receptor (IR) enzymes with achieving the lowest binding energy value. The present work suggests several of the compounds have the potential that contribute towards inhibiting α-glucosidase and DPP (IV) and thus effective in lowering post-prandial hyperglycaemia.

In this paper, bis (indol-3-yl) methanes (BIMs) were synthesised and evaluated for their inhibitory activity against α-glucosidase and α-amylase. All synthesised compounds showed potential α-glucosidase and α-amylase inhibitory activities. Compounds 5 g (IC 50 : 7.54 ± 1.10 μM), 5e (IC 50 : 9.00 ± 0.97 μM), and 5 h (IC 50 : 9.57 ± 0.62 μM) presented strongest inhibitory activities against α-glucosidase, that were ∼ 30 times stronger than acarbose. Compounds 5 g (IC 50 : 32.18 ± 1.66 µM), 5 h (IC 50 : 31.47 ± 1.42 µM), and 5 s (IC 50 : 30.91 ± 0.86 µM) showed strongest inhibitory activities towards α-amylase, ∼ 2.5 times stronger than acarbose. The mechanisms and docking simulation of the compounds were also studied. Compounds 5 g and 5 h exhibited bifunctional inhibitory activity against these two enzymes. Furthermore, compounds showed no toxicity against 3T3-L1 cells and HepG2 cells.HighlightsA series of bis (indol-3-yl) methanes (BIMs) were synthesised and evaluated inhibitory activities against α -glucosidase and α-amylase.Compound 5g exhibited promising activity (IC 50 = 7.54 ± 1.10 μM) against α -glucosidase.Compound 5s exhibited promising activity (IC 50 = 30.91 ± 0.86 μM) against α-amylase.In silico studies were performed to confirm the binding interactions of synthetic compounds with the enzyme active site.

Processing method is considered as a major factor that affects biotransformation of phytochemicals in tea and leads to diverse flavor and bioactivity of tea. In the present work, six typical tea manufacturing processings were employed to compare the effect on chemical composition of teas through using leaves of the single tea cultivar - - Camellia sinensis var. Meizhan. And in vitro antioxidant activity, inhibition against α-glucosidase and three lipid metabolism enzymes of these teas were also investigated, the relationships among them were analyzed further. As fresh leaves were processed into six categories of teas, the content of total catechins (TCs) has decreased in varying degrees while theaflavins (TFs) has increased. The antioxidant capacity composite index (ACCI) from high to low were green tea, yellow tea, oolong tea, white tea, dark tea, and black tea with the range from 98.44 to 58.38, which dominated by the content of TCs. Furthermore, all categories of teas possessed an inhibition effect on the pancreatic lipase (PL), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-COA reductase), lecithin cholesterol acyltransferase (LCAT), and α-glucosidase. The inhibition rate of PL and α-glucosidase appears to be positively influenced by TFs content (r =0.863, r =0.857, p < 0.05) while that of LCAT showed significant positive correlations with the content of tea polyphonels (TPs) (r = 0.902, p < 0.01). These results provide a better understanding of the relationships between processing method and chemical components of tea. It is suggested that various tea categories possess potential healthy effects which could serve as promising nutritional supplements.[Figure: see text].