Potent Α-glucosidase Inhibitors Research Articles

In silico exploration of the potential inhibitory activities of in-house and ZINC database lead compounds against alpha-glucosidase using structure-based virtual screening and molecular dynamics simulation approach

Inhibitors of α-glucosidase have been used to treat type-2 diabetes (T2DM) by preventing the breakdown of carbohydrates into glucose and prevent enhancing glucose conversion. Structure-based virtual screening (SBVS) was used to generate novel chemical scaffold-ligand α-glucosidase inhibitors. The databases were screened against the receptor α-glucosidase using SBVS and molecular dynamics simulation (MDS) techniques in this study. Based on molecular docking studies, three and two compounds of α-glucosidase inhibitors were chosen from a commercial database (ZINC) and an In-house database for this study respectively. The mode of binding interactions of the selected compounds later predicted their α-glucosidase inhibitory potential. Finally, one out of three lead compound from ZINC and one out of two lead compound from In-house database were shortlisted based on interactions. Furthermore, MDS and post-MDS strategies were used to refine and validate the shortlisted leads along with the reference acarbose/α-glucosidase. The Hits’ ability to inhibit α-glucosidase was predicted by SBVS, indicating that these compounds have good inhibitory activities. The lead inhibitor’s structure may serve as templates for the design of novel inhibitors, and in vitro testing to confirm their anti-diabetic potential is necessary. These insights can help rationally design new effective anti-diabetic drugs. Communicated by Ramaswamy H. Sarma

Studies of phytochemical constituents by UPLC-QTOF-MS/MS of black hulless barley bran and its antioxidation and α-glucosidase inhibition effect

Anthocyanidins and flavonoids are important components in plant. In present study, the anthocyanidins and flavonoids in black hulless barley bran were identified by operating UPLC-QTOF-MS/MS. Among them, chrysoeriol 7-O-glucouronid, luteolin 7-O-glucouronid, chrysoeriol, and luteolin were quantified by using UPLC. Additionally, the total phenolic content (TPC), total flavonoids content (TFC) and total anthocyanin content (TAC) were determined. Furthermore, the antioxidant activity (via ferric reducing, DPPH and ABTS method) and α-glucosidase inhibition effect were estimated. From the results, fifty-one constituents comprised 19 anthocyanidins and 32 flavonoids were detected in hulless barley bran fractions. Wherein compounds 1 and 9–19 (belong to anthocyanidins), and 21, 25–32, 35–42, 44–50 (belong to flavonoids) were first identified in hulless barley. The contents of chrysoeriol 7-O-glucouronid luteolin 7-O-glucouronid, chrysoeriol and luteolin were higher in E80% than that of in E40%, but were not detected in E20%. Another, the TAC exhibited the trend of E40% > E80% > E20%, and the TPC and TFC showed same trend of E40% > E20% > E80%. The higher TPC and TFC showed stronger antioxidant activity. However, no significant correlation between TAC, TPC, TFC and α-glucosidase inhibitory activity was observed. These results provided the anthocyanidins and flavonoids information, antioxidant value and α-glucosidase inhibition potential, which could provide reference in the development of black hulless barley bran.

Phomopamide A, a cyclic pentadepsipeptide with α-glucosidase inhibition activity from the endophytic fungus Diaporthe sp.

An undescribed cytotoxic cyclopeptide named phomopamide A (1) was isolated from Diaporthe sp., which is an endophytic fungus from Artemisia argyi. Phomopamide A (1) featured an pentadepsipeptide skeleton and composed of two Phe, one Val, one Leu, and one 2-hydroxyoctanoic acid units. The structure of this new compound was fully characterised on the basis of extensive spectroscopic analysis. Moreover, phomopamide A was evaluated for in vitro cyctotoxic and α-glucosidase inhibitory activity. As a result, phomopaminde A exhibited no cytotoxic activity against four tumour cell lines, while it showed a potent α-glucosidase inhibition effect with IC50 value of 62.35 µM.

Synthesis, structural characterizations, in vitro biological evaluation and computational investigations of pyrazole derivatives as potential antidiabetic and antioxidant agents

In this study, a two pyrazole derivatives; 2-(5-methyl-1H-pyrazole-3-carbonyl)-N-phenylhydrazine-1-carboxamide (Pyz-1) and 4-amino-5-(5-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-thiol (Pyz-2) were synthesized and characterized by 13C-NMR, 1H-NMR, FT-IR, and mass spectrometry. A complete molecular structures optimization, electronic and thermodynamic properties of Pyz-1 and Pyz-2 in gas phase and aqueous solution were predicted by using hybrid B3LYP method with the 6-311++G** basis sets. Pyz-1 and Pyz-2 were evaluated in vitro for their anti-diabetic, antioxidant and xanthine oxidase inhibition activities. For anti-diabetic activity, Pyz-1 and Pyz-2 showed a potent α-glucosidase and α-amylase inhibition with IC50 values of 75.62 ± 0.56, 95.85 ± 0.92 and 119.3 ± 0.75, 120.2 ± 0.68 µM, respectively, compared to Acarbose (IC50(α-glucosidase) = 72.58 ± 0.68 µM, IC50(α-amylase) = 115.6 ± 0.574 µM). In xanthine oxidase assay, Pyz-1 and Pyz-2 exhibited remarkable inhibitory ability with IC50 values 24.32 ± 0.78 and 10.75 ± 0.54 µM, respectively. The result of antioxidant activities showed that the title compounds have considerable antioxidant and radical scavenger abilities. In addition, molecular docking simulation was used to determine the binding modes and energies between the title compounds and α-glucosidase and α-amylase enzymes.

Retracted: Two Myricetin-Derived Flavonols from Morella rubra Leaves as Potent α-Glucosidase Inhibitors and Structure-Activity Relationship Study by Computational Chemistry.

[This retracts the article DOI: 10.1155/2022/9012943.].

TOWARDS UNDERSTANDING NATURAL ALPHA-GLUCOSIDASE INHIBITORS: A COMPUTATIONAL STUDY

Objective: Diabetes mellitus is a metabolic disorder affecting hundreds of millions of people around the world. It is characterized by hyperglycemia caused by impaired glucose homeostasis that results from insufficient insulin production or insulin resistance. There are clinically available α-glucosidase inhibitor drugs that are used to decrease postprandial blood glucose level. However, these drugs have side effects that necessitated the discovery of new α-glucosidase inhibitors with less side effects and high potency. The interest in the use of natural products to deal with diabetes has been increasing. Therefore, the potential of natural α-glucosidase inhibitors to inhibit the enzyme was investigated through computational methods. Material and Method: The binding potential of selected natural α-glucosidase inhibitors was investigated through molecular docking. Thereafter, the stability of the complexes with the highest binding potential were assessed through molecular dynamics (MD) simulation. Result and Discussion: The molecular docking demonstrated that compound 2 had better binding potential than the standard drug, acarbose. Compound 7 had comparable binding potential to the standard drug. Furthermore, all the tested compounds exhibited a reasonable binding potential towards the enzyme but were weaker than the standard drug. The MD simulation demonstrated that compounds 2 and 7 gave complexes with similar stability to the standard drug. The overall computational results revealed that the natural inhibitors investigated had the ability to bind to the enzyme and formed stable complexes. Therefore, these compounds could be potential α-glucosidase inhibitors for clinical use. For this reason, further in vitro investigations on compounds with the highest binding potential is recommended.

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.

Aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamides as potent α-glucosidase inhibitors; molecular dynamics, kinetic and structure–activity relationship studies

Regarding the important role of α-glucosidase enzyme in the management of type 2 diabetes mellitus, the current study was established to design and synthesize aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamide (11a–o) and the structure of all derivatives was confirmed through various techniques including IR, 1H-NMR, 13C-NMR and elemental analysis. Next, the α-glucosidase inhibitory potentials of all derivatives were evaluated, and all compounds displayed potent inhibition with IC50 values in the range of 26.0 ± 0.8–459.8 ± 1.5 µM as compared to acarbose used as control, except 11f and 11l. Additionally, in silico-induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the newly synthesized compounds over the active site of α-glucosidase.

Euclea natalensis Suppresses Postprandial Hyperglycemia in Rats via the Inhibition of α-Glucosidase: In vitro, in vivo, and Molecular Docking Studies

Background:: Postprandial hyperglycemia is a key factor in type 2 diabetes, and its management is critical in alleviating the deleterious consequences of diabetes and its associated micro and macrovascular complications. Objective:: The current study aims to determine the effect of Euclea natalensis leaf extracts on α- glucosidase inhibition in vitro and postprandial hyperglycemia in vivo in rats. Methods:: Sequentially extracted leaf extracts of Euclea natalensis were evaluated for their inhibitory effects on α-glucosidase in vitro and the suppression of postprandial hyperglycemia in normoglycemic rats. The extracts were fingerprinted using a Fourier-transform infrared spectrophotometer (FTIR), and the bioactive compounds were evaluated by molecular docking for their interaction with α-glucosidase. Results:: FTIR fingerprinting of the extracts showed that they contain functional groups of important bioactive phytochemicals. The extracts inhibited α-glucosidase in vitro, with the methanol extract (1 mg/mL) showing the highest inhibitory effect of 93.52 ± 1.50% compared to 69.62% ± 1.45 of the standard drug acarbose (0.05 mg/mL). The extracts also reduced postprandial hyperglycemia in rats in a sucrose tolerance test, where the hexane and methanol extracts performed similarly to Acarbose. Molecular docking studies showed that 20(29)-lupene-3β- isoferulate 3 is the most potent α-glucosidase inhibitor with the lowest binding energy of -10.79 kcal/mol, 2 hydrogen bonds with residues ASP1526 and ASP1157, and numerous Van der Waal interactions with amino acids in the binding pocket of α-glucosidase. Conclusion:: Euclea natalensis leaf extracts were found to suppress postprandial hyperglycemia by inhibiting α-glucosidase activity; thus, it has a promising potential for use as an antidiabetic agent.

Two new rotenoid glycosides from the rhizomes of Stemona curtisii Hook. f

Two new rotenoid glycosides named stemonal 11-O-β-D-glucopyranoside and 6-O-methylstemonal 11-O-β-D-glucopyranoside together with ten known metabolites were isolated from the rhizomes of Stemona curtisii. The chemical structures of the new compounds were elucidated based on the analysis of their 1D and 2D NMR and HRESIMS, while the sugar unit and absolute configuration were determined by chemical hydrolysis and ECD analysis. Among the tested compounds for anti-α-glucosidase assay, stemonal showed an inhibitory effect (IC50 = 38.67 µM), which is 2.4-fold more potent than acarbose. Cytotoxic evaluation against the lung adenocarcinoma A549 cell line indicated that none of the compounds were strongly active to suppress the cancer cell growth at 100 µM. This work describes the occurrence of rotenoids bearing a sugar moiety, which are reported for the first time in the genus Stemona. The isolated compound’s α-glucosidase inhibitory potential provides insight for further investigation of natural rotenoids as anti-diabetic agents.

Novel pyrazoline linked acyl thiourea pharmacophores as antimicrobial, urease, amylase and α-glucosidase inhibitors: design, synthesis, SAR and molecular docking studies.

In the present work, a small library of novel pyrazolinyl-acyl thiourea (5a-j) was designed and synthesized through a multistep sequence and the synthesized compounds were screened for their antifungal, antibacterial and antioxidant activities as well as urease, amylase and α-glucosidase inhibitory activities. The synthesized series (5a-o) was characterized using a combination of spectroscopic techniques, including FT-IR, 1H NMR and 13C NMR. All compounds (5a-j) were found to have significant potency against urease, α-glucosidase, α-amylase, and DPPH. The synthesized compounds were also screened for potential antibacterial and anti-fungal inhibition activities. IC50 values for all the prepared compounds for urease, α-glucosidase, amylase, and DPPH inhibition were determined and derivatives 5b and 5g were found to be the most potent urease inhibitors with IC50 values of 54.2 ± 0.32 and 43.6 ± 0.25 μM, respectively. Whilst compound 5b (IC50 = 68.3 ± 0.11 μM) is a potent α-glucosidase inhibitor, compound 5f (90.3 ± 1.08 μM) is a potent amylase inhibitor and compound 5b (103.4 ± 1.15 μM) is a potent antioxidant. The different substitutions on the phenyl ring were the basis for structure-activity relationship (SAR) study. The molecular docking study was performed for the confirmation of binding interactions.

Secondary metabolites from the leaves of Terminalia myriocarpa and their α-glucosidase inhibitory potential

The objective of this study is to investigate the chemical composition of the leaves of Terminalia myriocarpa and to evaluate their α-glucosidase inhibitory activity aiming to be used as a safe antidiabetic. Consequently, 10 compounds were isolated using column and preparative thin-layer chromatographic techniques and identified as alphitolic acid, isovitexin, flavogallonic acid, nigaichigoside F1, quercetin, quadranoside IV, rosamultin, 19α-hydroxyasiatic acid, asiatic acid, and arjunic acid. Structure elucidation was based on chemical (acid hydrolysis) and spectroscopic (UV, 1 H, and 13C-NMR) analyses and findings were confirmed through comparison with published data. The α-glucosidase inhibitory activity of the methanol extract fractions and compounds isolated therefrom was evaluated in-vitro alongside that of acarbose (positive control). Results revealed that quercetin and flavogallonic acid were significantly active with half-maximal inhibitory concentrations (IC50) equal to 7.5 ± 0.09 and 21.0 ± 1.4 µM, respectively. Furthermore, the interaction of lavogallonic acid with α-glucosidase enzyme was verified by docking experiment. Accordingly, quercetin and flavogallonic acid could be considered safer natural alternatives to the currently availableα-glucosidase inhibitors.

Quinoline-based Schiff bases as possible antidiabetic agents: ligand-based pharmacophore modeling, 3D QSAR, docking, and molecular dynamics simulations study.

α-Glucosidase enzyme inhibition is a legitimate approach to combat type 2 diabetes mellitus as it manages to control postprandial hyperglycemia. In this pursuit, a literature search identified quinoline-based molecules as potential α-glucosidase inhibitors. Thus our intended approach is to identify pharmacophoric features responsible for the α-glucosidase inhibition. This was achieved by performing, ligand-based pharmacophore modeling, 3D QSAR model development, pharmacophore-based screening of a rationally designed quinoline-based benzohydrazide Schiff base library, identifying, synthesizing and characterizing molecules (6a-6j) by IR, (1H and 13C) NMR, and mass studies. Further, these molecules were evaluated for α-glucosidase and α-amylase inhibitory potential. Compound 6c was found to inhibit α-glucosidase enzyme with an IC50 value of 12.95 ± 2.35 μM. Similarly, compound 6b was found to have an IC50 value of 19.37 ± 0.96 μM as compared to acarbose (IC50: 32.63 ± 1.07 μM); the inhibitory kinetics of compounds 6b and 6c revealed a competitive type of inhibition; the inhibitory effect can be attributed to its mapped pharmacophoric feature and model validation with a survival score of 5.0697 and vector score of 0.9552. The QSAR model showed a strong correlation with an R 2 value of 0.96. All the compounds (6a-6j) showed no toxicity in L929 cell lines by the MTT assay method. Further, the binding orientation and stability of the molecules were assessed using molecular docking studies and MD trajectory analysis. The energy profile of the molecules with protein as a complex and molecules alone was evaluated using MM/GBSA and DFT calculations, respectively; finally, the pharmacokinetic profile was computed using ADMET analysis.

Role of the thiosugar ring in the inhibitory activity of salacinol, a potent natural α-glucosidase inhibitor.

Herein, ring-cleaved (24) and truncated (25) analogues of an azasugar, 1-deoxynojirimycin (23), exhibited inhibitory activity (Ki = 4-10 μM) equal to that of the parent compound (1, Ki = 14 μM). Based on this structure-activity relationship (SAR), four ring-cleaved (26a-26c and 27c) and three truncated (28a-28c) analogues of salacinol (1), a potent thiosugar-ring-containing α-glucosidase inhibitor, were synthesised. Bioassay results revealed that all the synthetics were inactive, indicating that the 5-membered thiosugar ring of 1 played an essential role in the potent activities of sulfonium-type inhibitors. The present findings are interesting and important in understanding the function of salacinol, considering that the observed inhibitory activity trend was contrary to the SAR observed in aza-compounds (23, 24, and 25) in a previous study, which suggested that the cyclic structure did not contribute to their strong inhibitory activity.

Synthesis, biological activities, and evaluation molecular docking-dynamics studies of new phenylisoxazole quinoxalin-2-amine hybrids as potential α-amylase and α-glucosidase inhibitors.

New phenylisoxazole quinoxalin-2-amine hybrids 5a-i were successfully synthesised with yields of 53-85% and characterised with various spectroscopy methods. The synthesised hybrids underwent in vitro α-amylase and α-glucosidase inhibitory assays, with acarbose as the positive control. Through the biological study, compound 5h exhibits the highest α-amylase inhibitory activity with IC50 = 16.4 ± 0.1 μM while compounds 5a-c, 5e and 5h exhibit great potential as α-glucosidase inhibitors, with 5c being the most potent (IC50 = 15.2 ± 0.3 μM). Among the compounds, 5h exhibits potential as a dual inhibitor for both α-amylase (IC50 = 16.4 ± 0.1 μM) and α-glucosidase (IC50 = 31.6 ± 0.4 μM) enzymes. Through the molecular docking studies, the inhibition potential of the selected compounds is supported. Compound 5h showed important interactions with α-amylase enzyme active sites and exhibited the highest binding energy of -8.9 ± 0.10 kcal mol-1, while compound 5c exhibited the highest binding energy of -9.0 ± 0.20 kcal mol-1 by forming important interactions with the α-glucosidase enzyme active sites. The molecular dynamics study showed that the selected compounds exhibited relative stability when binding with α-amylase and α-glucosidase enzymes. Additionally, compound 5h demonstrated a similar pattern of motion and mechanism of action as the commercially available miglitol.

Synthesis, in vitro enzyme kinetics and molecular docking studies of the 2-formylphenyl sulfonates and their hydrazone derivatives as potential anti-diabetic and anti-inflammatory agents

The in vitro anti-diabetes and anti-inflammatory inhibitory activities of the synthesized 2-formylphenyl sulfonates and their hydrazone derivatives were evaluated through enzymatic assays as potential α-glucosidase and lipoxygenase (LOX-15) inhibitors. The preliminary inhibitory results obtained, revealed that the prepared compounds are good inhibitors of α-glucosidase as compared to lipoxygenase (LOX-15). Compounds 2 g and 3 h were found to exhibit significant inhibitory activities against α-glucosidase with IC50 values of 3.1 µM and 2.6 µM, respectively. Moderate inhibitory activity was also observed for compound 3a (IC50 = 7.3 µM) against this enzyme. Enzyme kinetics studies of the most active compound (3 h) suggested a mixed mode of inhibition for this compound against α-glucosidase. The molecular docking and molecular dynamics simulation of compounds 2 g, 3a and 3 h into the active sites of α-glucosidase were used to predict the binding modes and structure activity relationship for these compounds. The molecular dynamics simulation demonstrated that compound 3 h significant inhibitory activity is due to its ability to bind to both the catalytic and secondary sites of the enzyme.

In Vitro α-Amylase and α-Glucosidase Inhibitory Potential of Green Banana Powder Extracts.

This study investigated the proximate composition and inhibitory potential of hot water and ethanolic extracts of the pulp, peel and whole fruit of green banana (Musa sapientum) on α-amylase and α-glucosidase. Bioactive compounds were identified using GC-MS analysis. In addition, the cytotoxic effect on human gingival fibroblast (hGF) was evaluated using the sulphorhodamine B (SRB) assay. The results showed that the peel of green banana had the highest amount of ash (10.05%), fat (2.83%), protein (3.64%) and total dietary fibre (36.62%). The carbohydrate content of the whole fruit (81.79%) and pulp (81.50%) was higher than that of the peel (71.90%). The moisture content of the pulp (13.08%) was higher than that of the peel (11.58%) and whole fruit (11.30%). The ethanolic green banana peel extract showed a good inhibitory effect of α-amylase and α-glucosidase with the concentration necessary for 50% inhibition (IC50) of 0.512 and 0.100 mg·mL-1, respectively. The α-glucosidase inhibitory effect of the ethanolic green banana peel extract and the hot water green banana peel extract was not significantly different from that of acarbose (IC50 0.108 mg·mL-1). GC-MS analysis of the ethanolic green banana peel extract revealed fatty acids and fatty acid ester (9-octadecenamide (Z), octadecanamide and other compounds). The ethanolic peel extract exhibits a significant noncytotoxicity effect on hGF cells at concentrations ranging from 0.0001 to 1.0 mg·mL-1.

Rice bran peptide with α-glucosidase inhibition activity: Preparation, evaluation and molecular mechanism

The role of bioactive peptides in diabetes management has attracted extensive attention. In this study, the 1–3 kDa fraction of rice bran peptides (RBPs) was obtained by the hydrolysis of alkaline and dispase, and the following ultrafiltration demonstrated excellent α-glucosidase inhibition activity with an IC50 value of 1.17 ± 0.08 mg/mL and exhibited postprandial hypoglycemic activity in vivo. Enzymatic kinetics studies revealed that RBPs (1–3 kDa) inhibited α-glucosidase via competitive inhibition. Thirty-two peptides were characterized from RBPs (1–3 kDa) by LC-MS/MS. Virtual screening was applied to screening the new potential α-glucosidase inhibitor, and NVEKKDPTGA (NA-10) with a binding energy of −10.24 kcal/mol to α-glucosidase was selected as the most promising peptide. Molecular docking reflected that Ala at the C-terminal and KK amino acid cluster play a key role in forming hydrogen bonds with the catalytic site of α-glucosidase, which might be critical for the α-glucosidase inhibitory effect. This study proved that RBPs could be a promising bio-factor food ingredient for diabetes prevention.

Laxilignans A-C from the leaves of Terminalia laxiflora Engl. and their α-glucosidase inhibitory activity

Three previously undescribed dibenzylbutane lignans, laxilignans A−C, together with fifteen known compounds were isolated and characterized from the leaves of Terminalia laxiflora Engl. The structures of laxilignans A−C were elucidated by extensive 1D and 2D NMR analyses, together with mass spectrometry. The inhibitory activity of the isolated compounds against α-glucosidase enzyme, obtained from Saccharomyces cerevisiae, was evaluated in comparison to acarbose (IC50 = 16.42 ± 0.14 µM). The results revealed that corilagin, chebulagic acid, laxilignan A, termilignan B, termitomenin C, arjunglucoside II, and laxilignan B possess α-glucosidase inhibitory potential, with IC50 values in the range of 1.61 ± 0.05 – 403.5 ± 29.5 μM, respectively. The results of the molecular docking revealed that the two laxilignans A and B showed comparable binding affinities to those of acarbose with the binding sites of the human α-glucosidase enzyme. These findings suggest that dibenzylbutane lignans may act as promising lead compounds for the development of α-glucosidase inhibitors.

Carbonylbis(hydrazine-1-carbothioamide) derivatives as a new class of α-glucosidase inhibitors and their mechanistic insights via molecular docking and dynamic simulations.

In the past, efforts have been made to find a cure for diabetes, mainly evaluating new classes of compounds to explore their potency. In this study, we present the synthesis and evaluation of carbonylbis(hydrazine-1-carbothioamide) derivatives as potential α-glucosidase inhibitors, employing both in vivo and in silico investigations. The in vitro experiments revealed that all tested compounds were significantly potent for α-glucosidase inhibition, with the lead compound 3a displaying approximately 80 times higher activity than acarbose. To delve deeper, in silico induced fit docking, pharmacokinetics, and molecular dynamics studies were conducted. Significantly, compound 3a exhibited a docking score of -7.87 kcal/mol, surpassing acarbose, which had a docking score of -6.59 kcal/mol. The in silico ADMET indicated that most of the synthesized compounds have properties conducive to drug development. Molecular dynamics analysis demonstrated that, when the ligand 3a was coupled with the target 3TOP, Cα-RMSD backbone RMSD values below 2.4 Å and "Lig_fit_Prot" values below 2.7 Å were observed. QSAR analysis demonstrates that the "fOC8A" descriptor positively correlates with α-glucosidase inhibition activity, while "lipoplus_AbSA" positively contributes and "notringC_notringO_8B" negatively contributes to this activity.