Alpha-glucosidase inhibitory and hypoglycemic effects of imidazole-bearing thioquinoline derivatives with different substituents: In silico, in vitro, and in vivo evaluations.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of α-glucosidase, an enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as α-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). 8g as the most potent analog, indicating a competitive inhibition with Ki = 9.66 µM. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against α-glucosidase to determine its mode of action in the enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an α-glucosidase inhibitor for improving blood sugar control and metabolic health.

α-Glucosidase inhibition assay of galbanic acid and it amide derivatives: New excellent semi-synthetic α-glucosidase inhibitors.

α-Glucosidase inhibitory activity of galbanic acid and its new amide derivatives 3a-n were investigated. Galbanic acid and compounds 3a-n showed excellent anti-α-glucosidase activity with IC50 values ranging from 0.3 ± 0.3 µM to 416.0 ± 0.2 µM in comparison to positive control acarbose with IC50 value of = 750.0 ± 5.6. In the kinetic study, the most potent compound 3h demonstrated a competitive mode of inhibition with Ki = 0.57 µM. The interaction of the most potent compound 3h with the α-glucosidase was further elaborated by in vitro Circular dichroism assessment and in silico molecular docking and Molecular dynamics studies. Compound 3h was also non-cytotoxic on human normal cells. In silico study on pharmacokinetics and toxicity profile of the most potent galbanic acid derivatives demonstrated that these compounds are valuable lead compounds for further study in order to achieve new anti-diabetic agents.

New phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamides as dual inhibitors against α-glucosidase and PTP-1B for the treatment of type 2 diabetes.

This study describes the design, synthesis, and evaluation of a novel series of phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives (7a-l) as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1-B (PTB-1B). The latter enzymes are two important targets in the treatment of type 2 diabetes. The in vitro obtained data demonstrated that all title compounds 7a-l were more potent than the standard inhibitor acarbose against α-glucosidase while only four derivatives (7a, 7g, 7h, and 7h) were more potent than the standard inhibitor suramin against PTP-1B. Furthermore, these data showed that the most potent α-glucosidase inhibitor was compound 7i, with sixfold higher inhibitory activity than acarbose, and the most potent PTP-1B inhibitor was compound 7a with 3.5-fold higher inhibitory activity than suramin. Kinetic studies of compounds 7i and 7a revealed that they inhibited their target enzymes in a competitive mode. The docking study demonstrated that compounds 7i and 7a well occupied the active site pockets of α-glucosidase and PTP-1B, respectively. In silico pharmacokinetic and toxicity assays of the most potent compounds were performed, and the obtained results were compared with those of the standard inhibitors.

Arylureidoaurones: Synthesis, in vitro α-glucosidase, and α-amylase inhibition activity.

Because of the colossal global burden of diabetes, there is an urgent need for more effective and safer drugs. We designed and synthesized a new series of aurone derivatives possessing phenylureido or bis-phenylureido moieties as α-glucosidase and α-amylase inhibitors. Most of the synthesized phenylureidoaurones have demonstrated superior inhibition activities (IC50s of 9.6-339.9 µM) against α-glucosidase relative to acarbose (IC50 = 750.0 µM) as the reference drug. Substitution of aurone analogues with two phenylureido substituents at the 5-position of the benzofuranone moiety and the 3' or 4' positions of the 2-phenyl ring resulted in compounds with almost 120-180 times more potent inhibitory activities than acarbose. The aurone analogue possessing two phenylureido substitutions at 5 and 4' positions (13) showed the highest inhibition activity with an IC50 of 4.2 ± 0.1 µM. Kinetic studies suggested their inhibition mode to be competitive. We also investigated the binding mode of the most potent compounds using the consensually docked 4D-QSAR methodology. Furthermore, these analogues showed weak-to-moderate non-competitive inhibitory activity against α-amylase. 5-Methyl substituted aurone with 4'-phenylureido moiety (6e) demonstrated the highest inhibition activity on α-amylase with an IC50 of 142.0 ± 1.6 µM relative to acarbose (IC50 = 108 ± 1.2 µM). Our computational studies suggested that these analogues interact with a hydrophilic allosteric site in α-amylase, located far from the enzyme active site at the N-terminal.

Design, synthesis, in vitro, and in silico enzymatic evaluations of thieno[2,3-b]quinoline-hydrazones as novel inhibitors for α-glucosidase.

In the development of novel anti-α-glucosidase agents, we synthesized novel thieno[2,3-b]quinoline-hydrazones 9a-n by facile and efficient conventional chemical reactions. These compounds were characterized by IR, 1H NMR, 13C NMR, and elemental analysis. Inhibitory activities of the title compounds were evaluated against yeast α-glucosidase. In particular, compounds 9c, 9d, and 9h exhibited high anti-α-glucosidase activity. Representatively, compound 9c with IC50 = 1.3 µM, was 576-times more potent than positive control acarbose. Molecular docking study of the most active compounds showed that these compounds formed important binding interactions at α-glucosidase active site. Molecular dynamics study of compound 9c was also performed and the obtained results were compared with acarbose. Compounds 9c, 9d, and 9h were also evaluated for in silico druglikeness properties and ADMET prediction. These studies showed that the title most potent compounds could be exploited as drug candidates.

One-pot multi-component synthesis of novel chromeno[4,3-b]pyrrol-3-yl derivatives as alpha-glucosidase inhibitors.

A green and efficient one-pot multi-component protocol was developed for the synthesis of some novel dihydrochromeno[4,3-b]pyrrol-3-yl derivatives through the reaction of arylglyoxals, malono derivatives, and different 4-amino coumarins in ethanol at reflux condition. In this method, all products were obtained in good to excellent yield. Next, all synthesized derivatives were evaluated for their α-glucosidase inhibitory activity. Most of the compounds displayed potent inhibitory activities with IC50 values in the range of 48.65 ± 0.01-733.83 ± 0.10 µM compared to the standard inhibitor acarbose (IC50 = 750.90 ± 0.14 µM). The kinetic study of compound 5e as the most potent derivative (IC50 = 48.65 ± 0.01 µM) showed a competitive mechanism with a Ki value of 42.6 µM. Moreover, docking studies revealed that dihydrochromeno[4,3-b]pyrrol-3-yl effectively interacted with important residues in the active site of α-glucosidase.

Design and synthesis of phenoxymethybenzoimidazole incorporating different aryl thiazole-triazole acetamide derivatives as α-glycosidase inhibitors.

A novel series of phenoxymethybenzoimidazole derivatives (9a-n) were rationally designed, synthesized, and evaluated for their α-glycosidase inhibitory activity. All tested compounds displayed promising α-glycosidase inhibitory potential with IC50 values in the range of 6.31 to 49.89 µM compared to standard drug acarbose (IC50 = 750.0 ± 10.0 µM). Enzyme kinetic studies on 9c, 9g, and 9m as the most potent compounds revealed that these compounds were uncompetitive inhibitors into α-glycosidase. Docking studies confirmed the important role of benzoimidazole and triazole rings of the synthesized compounds to fit properly into the α-glycosidase active site. This study showed that this scaffold can be considered as a highly potent α-glycosidase inhibitor.

Laccase-loaded magnetic dialdehyde inulin nanoparticles as an efficient heterogeneous natural polymer-based biocatalyst for removal and detoxification of ofloxacin.

An efficient heterogeneous natural polymer-based biocatalyst was fabricated through the immobilization of laccase onto dialdehyde inulin (DAI)-coated silica-caped magnetic nanoparticles (laccase@DAI@SiO2@Fe3O4⋅MNPs). The carrier was developed using SiO2@Fe3O4⋅MNPs and functionalized with DAI. The construction of immobilized laccase was confirmed by scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Immobilization yield and efficiency were calculated as 61.0 ± 0.3% and 93.0 ± 0.6%, respectively. The immobilized laccase maintained 50% and 85% of its relative activity after 25 repeated cycles and 20 days of storage at 4 °C, respectively. The prepared biocatalyst effectively eliminated ofloxacin, a fluoroquinolone-type antibiotic, with a 63% removal capacity. Besides, antimicrobial activity study on some soil microorganisms involved in the biodegradation of xenobiotics revealed that the laccase-treated ofloxacin resulted in less toxic metabolites. The obtained data indicated that the fabricated biocatalyst is promising for the removal of ofloxacin or other analogs of fluoroquinolones in the environment.

Synthesis and biological evaluation of a new series of benzofuran-1,3,4-oxadiazole containing 1,2,3-triazole-acetamides as potential α-glucosidase inhibitors.

A series of new benzofuran-1,3,4-oxadiazole containing 1,2,3-triazole-acetamides 12a-n as potential anti-α-glucosidase agents were designed and synthesized. α-Glucosidase inhibition assay demonstrated that all the synthesized compounds 12a-n (half-maximal inhibitory concentration [IC50 ] values in the range of 40.7 ± 0.3-173.6 ± 1.9 µM) were more potent than standard inhibitor acarbose (IC50 = 750.0 ± 12.5 µM). Among them, the most potent compound was compound 12c, with inhibitory activity around 19-fold higher than acarbose. Since the most potent compound inhibited α-glucosidase in a competitive mode, a docking study of this compound was also performed into the active site of α-glucosidase. In vitro and in silico toxicity assays of the title compounds were also performed.

Synthesis, in vitro evaluation, and molecular docking studies of novel hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazole derivatives as potential α-glucosidase inhibitors.

In this work, a novel series of hydrazineylideneindolinone linked to phenoxymethyl-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their anti-α-glucosidase activity due to an urgent need to develop effective anti-diabetic agents. Among tested 15 compounds, 8 derivatives (9a, 9b, 9c, 9d, 9e, 9f, 9h, and 9o) demonstrated superior potency compared to that of positive control, acarbose. Particularly, compound 9d possessed the best anti-α-glucosidase activity with around a 46-fold improvement in the inhibitory activity. Additionally, 9d showed a competitive type of inhibition in the kinetic study and the molecular docking study demonstrated that it well occupied the binding pocket of the catalytic center through desired interactions with residues, correlating to the experimental results.

Synthesis, in-vitro evaluation, molecular docking, and kinetic studies of pyridazine-triazole hybrid system as novel α-glucosidase inhibitors.

In this study, we reported the discovery of pyridazine based 1,2,3-triazole derivatives as inhibitors of α-glucosidase. All target compounds exhibited significant inhibitory activities against yeast and rat α-glucosidase enzymes compared to positive control, acarbose. The most potent compound 6j, ethyl 3-(2-(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)ethyl)-5,6-diphenylpyridazine-4-carboxylate exhibited IC50 values of 58, and 73 µM. Docking studies indicated the responsibility of hydrophobic and hydrogen bonding interactions in the ligand-enzyme complex stability. The in-vitro safety against the normal cell line was observed by toxicity evaluation of the selected compounds.

Design and synthesis of novel quinazolinone-pyrazole derivatives as potential α-glucosidase inhibitors: Structure-activity relationship, molecular modeling and kinetic study.

In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 µM) in comparison to standard acarbose (IC50 = 750.0 ± 10.0 µM). Limited structure-activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 µM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme.

Quinazolinone-dihydropyrano[3,2-b]pyran hybrids as new α-glucosidase inhibitors: Design, synthesis, enzymatic inhibition, docking study and prediction of pharmacokinetic.

A series of new quinazolinone-dihydropyrano[3,2-b]pyran derivatives 10A-L were synthesized by simple chemical reactions and were investigated for inhibitory activities against α-glucosidase and α-amylase. New synthesized compounds showed high α-glucosidase inhibition effects in comparison to the standard drug acarbose and were inactive against α-amylase. Among them, the most potent compound was compound 10L (IC50 value = 40.1 ± 0.6 µM) with inhibitory activity around 18.75-fold more than acarboase (IC50 value = 750.0 ± 12.5 µM). This compound was a competitive inhibitor into α-glucosidase. Our obtained experimental results were confirmed by docking studies. Furthermore, the cytotoxicity of the most potent compounds 10L, 10G, and 10N against normal fibroblast cells and in silico druglikeness, ADME, and toxicity prediction of these compounds were also evaluated.

Synthesis of 4-alkylaminoimidazo[1,2-a]pyridines linked to carbamate moiety as potent α-glucosidase inhibitors.

In this work, various imidazo[1,2-a]pyridines linked to carbamate moiety were designed, synthesized, and evaluated for their α-glucosidase inhibitory activity. Among synthesized compounds, 4-(3-(tert-Butylamino)imidazo[1,2-a]pyridin-2-yl)phenyl p-tolylcarbamate (6d) was the most potent compound (IC50 = 75.6 µM) compared with acarbose as the reference drug (IC50 = 750.0 µM). Kinetic study of compound 6d indicated a competitive inhibition. Also, the molecular docking study suggested desired interactions with the active site residues. In particular, hydrogen bonds and electrostatic interactions constructed by compound 6d afforded well-oriented conformation in the 3A4A active site.

Design, synthesis, and α-glucosidase-inhibitory activity of phenoxy-biscoumarin-N-phenylacetamide hybrids.

Thirteen new phenoxy-biscoumarin-N-phenylacetamide derivatives (7a-m) were designed based on a molecular hybridization approach as new α-glucosidase inhibitors. These compounds were synthesized with high yields and evaluated in vitro for their inhibitory activity against yeast α-glucosidase. The obtained results revealed that a significant proportion of the synthesized compounds showed considerable α-glucosidase-inhibitory activity in comparison to acarbose as a positive control. Representatively, 2-(4-(bis(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenoxy)-N-(4-bromophenyl)acetamide (7f), with IC50 = 41.73 ± 0.38 µM against α-glucosidase, was around 18 times more potent than acarbose (IC50 = 750.0 ± 10.0 µM). This compound was a competitive α-glucosidase inhibitor. Molecular modeling and dynamic simulation of these compounds confirmed the obtained results through in vitro experiments. Prediction of the druglikeness/ADME/toxicity of the compound 7f and comparison with the standard drug acarbose showed that the new compound 7f was probably better than the standard drug in terms of toxicity.

An organic solvent-tolerant lipase of Streptomyces pratensis MV1 with the potential application for enzymatic improvement of n6/n3 ratio in polyunsaturated fatty acids from fenugreek seed oil.

Lipase-catalyzed esterification is an efficient technique in the production of polyunsaturated fatty acid (PUFA) concentrates which are applied for nutrition and health purposes. In this project, a solvent-tolerant lipase from Streptomyces pratensis MV1 was immobilized and purified by a hydrophobic support. The purified lipase revealed enhanced activity and stability towards chemicals, organic solvents, and a broad range of pH values. The production of lipase was enhanced to 7.0 U/mL after optimization by a central composite design. Acylglycerols (AGs) rich in α-linolenic acid (45%, w/w) were produced and a favorable n-6/n-3 free fatty acid (FFA) ratio of 1.1 was achieved in fenugreek seed oil using the immobilized lipase. The ability of S. pratensis lipase in ester synthesis and the improvement of n6/n3 FFA ratio make it a suitable candidate in food production industries.

Design and synthesis of novel pyridazine N-aryl acetamides: In-vitro evaluation of α-glucosidase inhibition, docking, and kinetic studies.

We herein applied the four step-synthetic route to prepare the pyridazine core attached to the various N-aryl acetamides. By this approach, a new series of pyridazine-based compounds were synthesized, characterized and evaluated for their activities against α-glucosidase enzyme. In-vitro α-glucosidase assay established that twelve compounds are more potent than acarbose. Compound 7a inhibited α-glucosidase with the IC50 value of 70.1 µM. The most potent compounds showed no cytotoxicity against HDF cell line. Molecular docking and kinetic studies were performed to determine the modes of interaction and inhibition, respectively.

Enzymatic dual-faced Janus structures based on the hierarchical organic-inorganic hybrid matrix for an effective bioremoval and detoxification of reactive blue-19.

A novel, dual-faced, and hierarchical type of Janus hybrid structures (JHSs) was assembled through an in situ growing of lipase@cobalt phosphate sheets on the laccase@copper phosphate sponge-like structures. The chemical and structural information of prepared JHSs was investigated by Scanning electron microscopy-energy dispersive X-ray analysis (SEM-EDX), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray diffraction analysis (XRD). The catalytic activity, storage stability, and reusability of JHSs were then investigated. The SEM-EDX analysis clearly confirmed the asymmetric morphology of the fabricated JHSs with two distinct metal distributions. Under optimized synthesis conditions, the prepared JHSs showed 97.8 % and 100 % of laccase and lipase activity, respectively. Compared to the free biocatalysts, the immobilization resulted in ~ a 2-fold increase in laccase and lipase stability at temperatures of >40 °C. The fabricated JHSs maintained 61 % and 90 % of their original laccase and lipase activity upon 12 successive repetition cycles. Up to 80 % of Reactive Blue-19 (RB-19), an anthraquinone-based vinyl sulphone dye, was removed after 5 h treatment with the prepared JHSs (50 % higher than the free forms of laccase and lipase). The dye removal data fitted very well on the pseudo-second-order kinetic model with a rate constant of 0.8 g mg-1 h-1. Following the bioremoval process, bacterial toxicity also decreased by about 70 %. Therefore, the prepared JHSs provide a facile and sustainable approach for the decolorization, biotransformation, and detoxification of RB-19 by integrating enzymatic oxidation and hydrolysis.

Surface functionalization of endotracheal tubes coated with laccase-gadolinium phosphate hybrid nanoparticles for antibiofilm activity and contrasting properties.

Ventilator-associated pneumonia (VAP) is a severe hospital-acquired infection that endangers patients' treatment in intensive care units (ICUs). One of the leading causes of VAP is biofilm formation on the endotracheal tube (ETT) during ventilation. This study reports a combination of laccase-gadolinium phosphate hybrid nanoparticles (laccase@GdPO4·HNPs) and enzyme mediator with an antibiofilm property coated on the surface of the ETT. The hybrid nanostructures were fabricated through a simple, rapid, and facile laccase immobilization method, resulting in efficiency and yield percentages of 82 ± 6% and 83 ± 5%, respectively. The surface of the ETT was then functionalized and coated with the constructed HNP/catechol. The layered ETT was able to reduce the surface adhesion of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus by 82.1%, 84.5%, and 77.1%, respectively. The prepared ETT did not affect the viability of human lung epithelial cells L929 and A549 at concentrations of 1-5 mg mL-1. The layered ETT produced a strong computed tomography (CT) signal in comparison with iobitridol. The HNP/catechol-coated ETT exhibited a Gd3+ release of 0.45 ppm over 72 h, indicating reduced risks of cytotoxicity arising from the metal ions. In this research we develop a biofilm-resistant and contrasting agent-based ETT coated with green synthesized laccase@GdPO4·HNPs.

Synthesis, in vitro potency of inhibition, enzyme kinetics and in silico studies of quinoline-based α-glucosidase inhibitors.

Diabetes mellitus is a multifactorial global health disorder that is rising at an alarming rate. One effective therapeutic approach for controlling hyperglycemia associated with type-2 diabetes is to target α-glucosidase, which catalyzes starch hydrolysis in the intestine. In an attempt to find potential α-glucosidase inhibitors, a series of twenty new quinoline linked benzothiazole hybrids (8a-t) were synthesized in good yields from suitable reaction procedures and their chemical structures were analyzed by 1HNMR, 13CNMR, IR, and ESI-MS analysis. The synthesized derivatives further screened for their activity against α-glucosidase. Among them, compounds 8b, 8h, 8n and 8o exhibited remarkable α-glucosidase inhibitory activity with IC50 values ranging from 38.2 ± 0.3 to 79.9 ± 1.2 µM compared with standard drug acarbose (IC50 = 750.0 ± 2.0 µM). Enzyme kinetic studies of the most active compound (8h) indicated a non-competitive inhibition with Ki value of 38.2 µM. Moreover, the homology modeling, molecular docking and molecular dynamics simulation studies were conducted to reveal key interactions between the most active compound 8h and the targeted enzyme. These results are complementary to the experimental observations. In order to predict the druggability of the novel derivatives, the pharmacokinetic properties were also applied. These findings could be useful for the design and development of new α-glucosidase inhibitors.