Standard Drug Acarbose Research Articles

Synthesis and Molecular Docking of Curcumin-Derived Pyrazole-Thiazole Hybrids as Potent α-Glucosidase Inhibitors.

α Glucosidase inhibitors are critical for diabetes management, with pyrazoles and thiazoles emerging as effective options. This research highlights curcumin-based pyrazole-thiazole hybrids as potential inhibitors, synthesizing derivatives and evaluating their inhibitory capabilities. The study involved the synthesis of novel compounds using hydrazonoyl halides, confirmed through elemental and spectral analyses. The synthesized derivatives exhibited significant α-glucosidase inhibition, with IC50 values ranging from 3.37 ± 0.25 to 16.35 ± 0.37 µM. Among them, compound 7e demonstrated the strongest inhibition at 3.37 ± 0.25 µM, outperforming the standard drug acarbose (IC50 = 5.36 ± 0.31 µM). In silico assessments and molecular docking using AutoDock Vina revealed strong interactions, particularly with compounds 7b, 7e, 7f, and 7g, indicating their potential as stable and effective inhibitors. The results suggest that the synthesized pyrazole-thiazole hybrids hold promise as novel therapeutic agents for diabetes, warranting further exploration of their substituent effects for optimized inhibitor design.

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

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

α-Glucosidase Inhibiting Chromene Derivatives from Ageratum conyzoides L. Essential Oil Extracted via NADES-Assisted Hydrodistillation.

This work employed a green approach utilizing natural deep eutectic solvent (NADES)-assisted hydrodistillation for EO extraction from the aerial part of Ageratum conyzoides. Out of seven eutectic combinations used, glycerol-lactic acid (GLY:LA) (1:1) mixture significantly enhanced the yield from 0.78 mg/g (water as extraction media) to 1.00 mg/g. GC and GC-MS analysis revealed that EOs mainly contain (E)-β-caryophyllene (15.2-25.3%), (E)-β-farnesene (2.7-8.2 %), and notably, precocene-I (8.5-18.0 %) and precocene-II (31.8-51.4 %), which varied significantly across different extraction media. Further column chromatography-based purification of EO led to the isolation of two known chromene derivatives precocene-I (1) and precocene-II (2). Precocene-I exhibited potent anti-diabetic activity (IC50 0.26 mg/mL) compared to the standard drug acarbose. Among the EO samples, USK-N7, which had the highest percentage of precocene-I, showed the highest activity. The present study demonstrated the potential use of this weed plant as an anti-diabetic agent.

Synthesis, Characterization, and Antidiabetic Evaluation of N-((5-(3- chloro-4-nitrophenyl)-1,3,4-oxadiazol-2-yl) carbamothioyl) Benzamide Derivatives.

A series of novel N-((5-(3-chloro-4-nitrophenyl)-1,3,4-oxadiazol-2-yl) carbamothioyl) benzamide derivatives (2a-2h) were synthesized and characterized for their potential antidiabetic properties. The synthesis involved multi-step reactions starting from 3-chloro-4-nitrobenzoic acid, and the final compounds were purified by recrystallization. The structures were confirmed using melting points, TLC, FTIR, 1 H-NMR, 13C-NMR, and LC-MS. In-silico pharmacokinetic analysis using SwissADME indicated favorable drug-likeness properties for the synthesized compounds, particularly those with electron-withdrawing substituents. In-vitro assays demonstrated significant α-amylase and α-glucosidase inhibitory activities, with compounds 2a, 2g, and 2h showing the highest potency (IC50 values: 23.19-28.61 µM for α-amylase and 23.25-28.25 µM for α-glucosidase), comparable to the standard drug acarbose. The presence of electron-withdrawing groups enhanced the inhibitory effects, while electron-donating groups reduced efficacy. These findings suggest that the synthesized compounds, particularly 2a, 2g, and 2h, hold promise as effective antidiabetic agents.

Design, synthesis, biological evaluation and molecular docking study of thiadiazole-isatin hybrid analogues as potential anti-diabetic and anti-bacterial agents

We have synthesized thiadiazole-isatin hybrid analogues (1–20), characterized through different spectroscopic techniques such as 1HNMR, 13CNMR, HREI-MS, and evaluated against α-glucosidase and α-amylase enzymes. All analogues showed potent inhibitory potentials, having an IC50 values ranged from 22.08 ± 0.09 to 54.03 ± 0.07 μM (against α-amylase) and 19.03 ± 0.04 to 50.03 ± 0.02 μM (α-glucosidase) when compared with the standard drug acarbose (IC50 = 22.07 ± 0.02 μM for α-amylase and IC50 = 18.01 ± 0.06 μM for α-glucosidase respectively). Among the series, analogues 13 (IC50 = 19.03 ± 0.04 and 22.08 ± 0.09 μM), 12 (IC50 = 21.03 ± 0.07 and 24.03 ± 0.07 μM), and 5 (IC50 = 22.02 ± 0.03 and 26.02 ± 0.04 μM) were identified as the most active inhibitors. The structure–activity relationship was carried out, mainly associated with the nature, number, position, and electron-donating and electron-withdrawing effects of the substituent (s) on the phenyl ring. With the help of molecular docking, the binding interaction of the most active analogues within the active site of enzymes was confirmed. Almost twelve compounds were also screened for antibacterial potential, and few were found to be effective against Bacillus subtilis. All compounds were verified for cytotoxicity against the 3 T3 mouse fibroblast cell line and detected non-toxic.

Pyridazine Derivatives as New Antidiabetic Agents: Synthesis, In‐Vitro α‐Amylase Inhibitory Activity, Molecular Docking and Molecular Dynamics Simulations Studies

AbstractThis study involved the synthesis, characterization, and assessment of fourteen pyridazine analogs (designated as 1–14) to investigate their efficacy in inhibiting the α‐amylase enzyme for potential diabetes treatment using an in vitro approach. Additionally, in silico molecular docking and molecular dynamic (MD) simulations were conducted to assess the inhibitory properties of these analogs. Physicochemical and pharmacokinetic properties of the fourteen pyridazine analogs were predicted using the DataWarrior tool. Results indicated that all tested compounds demonstrated significant α‐amylase inhibitory activity, with IC50 values ranging from 81.28±0.00 to 1623.54±2.67 μM compared to the standard drug acarbose (IC50=220.42±36.40 μM). Notably, compounds 8 and 12 exhibited the most potent α‐amylase inhibitory activity, with IC50 values of 81.28±0.00 μM and 200.60±34.65 μM, respectively. Molecular docking analysis revealed binding energies ranging from −7.53 to −5.77 kcal/mol and inhibition constants ranging from 3.00 to 58.96 μM, with compounds 9, 7, 8, 5, and 3 demonstrating the best binding energies. Subsequent MD simulation analyses indicated that all five compound formed stable complexes after 100 ns MD simulation. Consequently, these compounds hold promise as potential α‐amylase inhibitors pending successful clinical validation.

Access to Isoxazoles via Photo-oxygenation of Furan Tethered α-Azidoketones.

Photocatalyst-free visible light-enabled direct oxygenation of furan-tethered α-azidoketones was studied. The reaction yielded various products depending on the substituents, with isoxazoles forming as the major products. The findings suggest that singlet oxygen was generated during the reaction and reacted with α-azidoketones in a [4 + 2] fashion to yield endoperoxides, which rearranged in multiple ways to generate isoxazoles. Some of the synthesized isoxazoles were evaluated as α-glucosidase inhibitors, and three of them 5bi, 5bj, and 5bl exhibited good activity with IC50 values of 454.57 ± 29.34, 147.84 ± 2.28, and 272.58 ± 42.06 μM, respectively, when compared with the standard drug acarbose (IC50 = 1224.33 ± 126.72 μM).

Molecular hybridization, synthesis, in vitro α-glucosidase inhibition, in vivo antidiabetic activity and computational studies of isatin based compounds

In the pursuit of novel antidiabetic agents, a series of isatin-thiazole derivatives (7a-7j) were synthesized and characterized using a range of spectroscopic techniques. The enzyme inhibitory activities of the target analogues were assessed using both in vitro and in vivo assays. The tested compounds 7a-7j demonstrated In vitro inhibitory potential against α-glucosidase, as indicated by their IC50 values ranging from 28.47 to 46.61 µg/ml as compared to standard drug acarbose IC50 value of 27.22 ± 2.30 µg/ml. Additionally, compounds 7d and 7i were chosen for in vivo evaluation of their antidiabetic efficacy in streptozotocin-induced diabetic Wistar rats. These compounds exhibited significant antidiabetic activity both in vitro and in vivo, compound 7d produces therapeutic effects compared to standard pioglitazone by decreasing glycaemia and triglyceride levels in diabetic animals. Furthermore, a molecular docking study was conducted to elucidate the binding interactions of the compounds within the α-glucosidase enzyme binding pocket (PDB ID 3A47) and stability was confirmed by dynamics simulation trajectories. Thus, from the above findings, it may demonstrate that isatin-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.

Evaluations of the in vitro and in vivo antidiabetic activity of 70 % ethanolic fruit extracts of Rosa abyssinica

BackgroundDiabetes mellitus is becoming major health challenge with continually increasing burden. High costs of conventional medicines and numerous side effects associated with them, on the other hand, easy availability and accessibility of traditional herbal medicines calls upon experimental investigations to validate their effect on lowering blood glucose level. MethodsThe dried fruit of Rosa abyssinica was macerated with 70 % ethanol and the extract's in vitro antidiabetic activity was investigated using dinitrosalisylic acid method for alpha amylase inhibitory activity. Furthermore, the in vivo hypoglycemic and Antihyperglycemic effects of various doses of the extract (100, 200 and 400 mg/kg) was determined on normoglycemic, glucose loaded (1500 mg/kg) and Streptozotocine (180 mg/kg)-induced diabetic mice models. ResultsThe acute oral toxicity study revealed the plant showed no toxic effect on swiss albino mice at 2000 mg/kg. The in vitro alpha amylase inhibitory activity study showed that the extract has comparable IC50 value of 21.37 ± 4.252 μg/ml with the standard drug acarbose (IC50 value of 26.72 ± 3.59 μg/ml). On the other hand, in normal mice, none of the dose levels except at 400 mg/kg significantly reduces blood glucose level. This is in contrast to the oral glucose tolerance test, which the extract produced significant reduction at 60, 90 and 120 min following glucose challenge. The 70 % ethanolic fruit extracts of Rosa abyssinica also experienced profound antidiabetic activity in streptozotocin-induced diabetic model. In the single-dose study, both RAFE200 and RAFE400 demonstrated a significant (P˂0.05) reduction in blood glucose levels at 1, 2, 3, and 4 h. Similarly, in the repeated-dose study, RAFE200 and RAFE400 not only significantly reduced blood glucose levels but also produced a notable improvement in animal body weight. ConclusionThe 70 % ethanolic fruit extracts of Rosa abyssinica have shown significant in vitro alpha amylase inhibition effect and an in vivo blood glucose level lowering effects in diabetic mice.Therefore, this study supports the traditional use of Rosa abyssinica in the management of diabetes mellitus.

Design, synthesis, α-glucosidase inhibition and hypoglycemic activity of 3-aceto(benzo)hydrazide-1,2,4-triazines as potential anti-diabetic agents

Type 2 diabetes is a common condition that causes the level of glucose in the blood to become too high and α-glucosidase inhibitors are therapeutic agents in managing type 2 diabetes. In the present study, we report a new series of 3-aceto(benzo)hydrazide-1,2,4-triazine analogs as potential therapeutic agents against type 2 diabetes. In the in vitro evaluations, most compounds showed much stronger α-glucosidase inhibitory activity than the standard drug acarbose. Especially, compound 2A, (N'-(5,6-diphenyl-1,2,4-triazin-3-yl)-4-methoxybenzohydrazide) as the most active compound showed IC50 = 12.0 μM which is 60 folds more potent than acarbose. In addition, the MTT test using the three cell lines HCT-116, MDA-MB-231, and A549 showed that the target compounds have low cytotoxic effects with IC50 values in the range of 60–280 μM, therefore they can be considered as safe compounds. Molecular docking studies predicted that the strong inhibitory activity of 2A is related to the interactions generated by the three residues Asp282, Trp481, and Asp616 with the triazine core and hydrazide motif in the active site of the enzyme. The significant inhibitory effect of 2A against α-glucosidase was also confirmed in vivo, where the compound showed equivalent activity to the standard drug acarbose on reducing blood glucose in the tested mice. In conclusion, this study introduces compound 2A as a new lead compound with favorable cytotoxicity, strong α-glucosidase inhibitory activity and in vivo hypoglycemic effect, for future investigation in the treatment of diabetes mellitus.

Curbing Key Digestive Enzymes by Three Plant Extracts for Sustainable Management of Postprandial Hyperglycemia

Background: Diabetes mellitus is a chronic metabolic condition marked by persistently elevated blood sugar levels. Key digestive enzymes viz. α-amylase and α-glucosidase, hydrolyze consumed carbohydrates into glucose which raises the postprandial blood glucose level in a diabetic patient. So, the development of α-amylase and α-glucosidase inhibitors procured from medicinal plants to retard starch digestion is an alternative approach for controlling type 2 diabetes mellitus. Objective: The current study aimed to evaluate the inhibitory potentials of the key digestive enzymes viz. α-amylase and α-glucosidase by the extracts of three medicinal plants; red dragon fruit (Hylocereus polyrhizus) pulp and peel, bamboo (Bambusa vulgaris) shoot, turnip (Brassica rapa L.) shoot and leaf by performing α-amylase and α-glucosidase inhibition assays in vitro. Methods: Inhibition of α-amylase activity was conducted using 3,5-dinitrosalicylic acid method, and 4- Nitrophenyl-α-D-glucopyranoside was used as a substrate to perform α-glucosidase inhibition assay in vitro. Results: Among all the selected sample extracts, red dragon fruit pulp expressed the highest percentage of α-amylase inhibition (59.73 ± 4.33%) at the concentration of 1000 μg/mL which is comparable to standard antidiabetic drug Acarbose (70.59 ± 2.64%), whereas the lowest inhibition was observed in turnip shoot extract (42.48 ± 2.10%) at the same concentration. In terms of α-glucosidase inhibition activity, again, red dragon fruit pulp extract demonstrated the maximum inhibition rate (56.42 ± 2.38%) at 1000 μg/mL concentration. This is respectable in comparison to the reference Acarbose (66.45 ± 1.78%). In contrast, turnip shoot extracts displayed the lowest α-glucosidase inhibition activity (38.27 ± 2.21%) at the same concentration. Conclusion: The current study demonstrated that the red dragon fruit pulp extract possesses substantial antihyperglycemic activity (α-amylase inhibition: 59.73 ± 4.33%, α-glucosidase inhibition: 56.42 ± 2.38%) in vitro, which could be a putative nutraceutical to manage postprandial hyperglycemia.

Synthesis, Computational Study, and In Vitro α-Glucosidase Inhibitory Action of Thiourea Derivatives Based on 3-Aminopyridin-2(1H)-Ones.

Reactions with allyl-, acetyl-, and phenylisothiocyanate have been studied on the basis of 3-amino-4,6-dimethylpyridine-2(1H)-one, 3-amino-4-phenylpyridine-2-one, and 3-amino-4-(thiophene-2-yl)pyridine-2(1H)-one (benzoyl-)isothiocyanates, and the corresponding thioureide derivatives 8-11a-c were obtained. Twelve thiourea derivatives were obtained and studied for their anti-diabetic activity against the enzyme α-glucosidase in comparison with the standard drug acarbose. The comparison drug acarbose inhibits the activity of α-glucosidase at a concentration of 15 mM by 46.1% (IC50 for acarbose is 11.96 mM). According to the results of the conducted studies, it was shown that alkyl and phenyl thiourea derivatives 8,9a-c, in contrast to their acetyl-(benzoyl) derivatives and 10,11a-c, show high antidiabetic activity. Thus, 1-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9a has the highest inhibitory activity against the enzyme α-glucosidase, exceeding the activity of the comparison drug acarbose, which inhibits the activity of α-glucosidase by 56.6% at a concentration of 15 mm (IC50 = 9,77 mM). 1-(6-methyl-2-oxo 4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9c has inhibitory activity against the enzyme α-glucosidase, comparable to the comparison drug acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mm per 41.2% (IC50 = 12,94 mM). Compounds 8a, 8b, and 9b showed inhibitory activity against the enzyme α-glucosidase, with a lower activity compared to acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mM by 23.3%, 26.9%, and 35.2%, respectively. The IC50 against α-glucosidase for compounds 8a, 8b, and 9b was found to be 16.64 mM, 19.79 mM, and 21.79 mM, respectively. The other compounds 8c, 10a, 10b, 10c, 11a, 11b, and 11c did not show inhibitory activity against α-glucosidase. Thus, the newly synthesized derivatives of thiourea based on 3-aminopyridine-2(1H)-ones are promising candidates for the further modification and study of their potential anti-diabetic activity. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models.

Synthesis, α-glucosidase inhibitory activity, and molecular dynamic simulation of 6-chloro-2-methoxyacridine linked to triazole derivatives

Α-glucosidase inhibition can be useful in the management of carbohydrate-related diseases, especially type 2 diabetes mellitus. Therefore, in this study, a new series of 6-chloro-2-methoxyacridine bearing different aryl triazole derivatives were designed, synthesized, and evaluated as potent α-glucosidase inhibitors. The most potent derivative in this group was 7h bearing para-fluorine with IC50 values of 98.0 ± 0.3 µM compared with standard drug acarbose (IC50 value = 750.0 ± 10.5 μM). A kinetic study of compound 7h revealed that it is a competitive inhibitor against α-glucosidase. Molecular dynamic simulations of the most potent derivative were also executed and indicated suitable interactions with residues of the enzyme which rationalized the in vitro results.

Investigation of pyridine-bearing thiazolidinone derivatives as promising inhibitors of thymidine phosphorylase and α-glucosidase: Theoretical and computational approaches to develop multitarget drugs

The present study reports the new pyridine-containing analogs bearing thiazolidinone moieties (1–15), which were synthesized and their biological activity was assessed against thymidine phosphorylase and α-glucosidase enzymes. Some of the analogues with the same basic structure but different substituents were discovered to have strong potential against the targeted enzymes, while other analogues were found to have medium to moderate activity in the tested series. These analogues showed a varied range of inhibition in the case of thymidine phosphorylase, 1 (IC50 = 5.70 ± 0.20 µM), 5 (IC50 = 4.50 ± 0.50 µM), 6 (IC50 = 4.60 ± 0.20 µM) and 12 (IC50 = 6.30 ± 0.20 µM), compared with standard 7-Deazaxanthine, 7DX (IC50 = 32.68 ± 1.20 µM). Similarly, excellent inhibitory profiles were also shown by these analogues in the case of alpha-glucosidase inhibition activity, 1 (IC50 =1.80 ± 0.20 µM), 5 (IC50 =1.40 ± 0.10 µM) 6 (IC50 =2.50 ± 0.60 µM) and 12 (IC50 =3.10 ± 0.30 µM) when compared with standard drug acarbose (IC50 = 3.30 ± 1.30 µM). These analogues were also subjected to molecular docking studies against using the PDB id of 1UOU for thymidine phosphorylase (PDB Id: 1UOU) and alpha-glucosidase ((PDB Id: 3w37), for exploration of binding interactions of molecules with active site of the enzymes. ADME studies also predicted the drug-like properties of these analogues.

Discovery of Novel and Selective Schiff Base Inhibitors as a Key for Drug Synthesis, Molecular Docking, and Pharmacological Evaluation.

Diabetes mellitus (DM) is a chronic disorder and still a challenge throughout the world, and therefore the search for safe and effective inhibitors for α-amylase and α-glucosidase is increasing day by day. In this work, we try to carry out the synthesis, modification, and computer-aided results of and biological research on thiadiazole-based Schiff base derivatives and evaluate their in vitro α-amylase and α-glucosidase inhibitory potential (1-15). In the current series, all of the synthesized analogues were shown to have potential inhibitory effects on targeted enzymes. The IC50 values for α-amylase values ranged from 20.10 ± 0.40 to 0.80 ± 0.05 μM, compared with the standard drug acarbose having an IC50 value of 10.30 ± 0.20 μM, while for α-glucosidase, the IC50 values ranged from 20.10 ± 0.50 to 1.20 ± 0.10 μM, compared to acarbose with an IC50 value of 9.80 ± 0.20 μM. For better understanding, a SAR investigation was undertaken. In this series, nine scaffolds (1, 2, 3, 6, 9, 10, 11, 13, and 15) were more active than the reference drug and the docking parameter RMSD values for α-glucosidase and α-amylase were 1.766, 2.7746, 1.6025, 2.2112, 3.5860, 2.3360, 1.6178, 2.0254, and 2.0797 and 2.6020, 1.9509, 3.1642, 1.7547, 2.2130, 1.4221, and 1.1087, respectively. The toxicity of the selected analogues was calculated by using the OSIRIS tool, and the TPSA values were found to be lower than 140 to represent the drug-like properties; those from Molinspiration were studied as well. The following properties were studied and found to have better biological properties. The remaining analogues (4, 5, 7, 8, 12, and 14) were also identified as potential inhibitors of both enzymes, but they were less active than the reference due to the substituents attached to the aromatic parts. The structures of synthesized compounds were confirmed through different spectroscopic analyses.

Design, Synthesis, Biological Evaluation and Docking, ADME Studies of Novel Phenylsulfonyl Piperazine Analogues as α-Amylase Inhibitors

Diabetes mellitus (DM) stands as one of the most widespread diseases encountered today. It is primarily characterized by diminished insulin levels and heightened blood glucose concentrations. Inhibition of the α-amylase enzyme plays a pivotal role in the management of diabetes mellitus. Piperazine and sulfonamide groups are recognized for their extensive range of biological effects. The current study involved synthesizing five phenylsulfonyl piperazine derivatives. An evaluation of their α-amylase inhibitory capacities was conducted. Phenylsulfonyl piperazine derivatives (compounds 1-5) exhibited notable α-amylase enzymatic inhibition, with compound 4 showing the most substantial potential for inhibition. The inhibitory percentage of compound 4 (80.61±0.62) surpassed that of the standard drug acarbose (78.81±0.02). The molecular docking studies identified compound 4 as possessing the most substantial inhibitory effect on the α-amylase enzyme, with notable binding energy -8.2 kcal/mol. This compound exhibited specific interactions, including π-π stacking and π-anion interactions with key enzyme residues, solidifying its role as a potent inhibitor

Synthesis of thiazolidine-2,4-dione tethered 1,2,3-triazoles as α-amylase inhibitors: In vitro approach coupled with QSAR, molecular docking, molecular dynamics and ADMET studies

A new series of thiazolidine-2,4-dione tethered 1,2,3-triazole derivatives were designed, synthesized and screened for their α-amylase inhibitory potential employing in vitro and in silico approaches. The target compounds were synthesized with the help of Cu (I) catalyzed [3 + 2] cycloaddition of terminal alkyne with numerous azides, followed by unambiguously characterizing the structure by employing various spectroscopic approaches. The synthesized derivatives were assessed for their in vitro α-amylase inhibition and it was found that thiazolidine-2,4-dione derivatives 6e, 6j, 6o, 6u and 6x exhibited comparable inhibition with the standard drug acarbose. The compound 6e with a 7-chloroquinolinyl substituent on the triazole ring exhibited significant inhibition potential with IC50 value of 0.040 μmol mL−1 whereas compound 6c (IC50 = 0.099 μmol mL−1) and 6h (IC50 = 0.098 μmol mL−1) were poor inhibitors. QSAR studies revealed the positively correlating descriptors that aid in the design of novel compounds. Molecular docking was performed to investigate the binding interactions with the active site of the biological receptor and the stability of the complex over a period of 100 ns was examined using molecular dynamics studies. The physiochemical properties and drug-likeliness behavior of the potent derivatives were investigated by carrying out the ADMET studies.

Synthesis, in vitro α-glucosidase inhibitory potential and in silico study of 2‑chloro pyridine incorporated thiosemicarbazones

Diabetes is a devastating metabolic illness that affects people of all ages and is widespread around the world as a result of the malfunctioning of prior treatment approaches. This work attempts to treat type 2 diabetes mellitus (T2DM) by outlining the design, synthesis, in vitro and in silico assessment of 2-Nicotinaldehyde-based thiosemicarbazones as possible inhibitors of α-glucosidase. The synthesized derivatives 3(a-m) displayed excellent to good inhibitory potential against standard drug acarbose (IC50 = 4.10 ± 0.16 µM to 32.76 ± 0.80 µM. Among these compounds 3m displayed highest inhibition activity with IC50 value of 4.10 ± 0.16 µM. SAR of the derivatives have shown that the compounds with meta substitution displayed better activity than the para substitution. In order to obtain more profound understanding, molecular dynamics, and in silico molecular docking simulations were performed to examine the interactions, stability, orientation, and conformation of the synthesized derivatives inside the α-glucosidase active pocket.

Synthesis, biological evaluation and in silico molecular modelling studies of chloro substituted bis-indole containing benzohydrazide analogues as potential anti-diabetic and anti-Alzheimer's agents

Fifteen bis-indolylmethane analogues were synthesized, characterized through NMR (1H, 13C) and high-resolution electron-impact mass spectrometry (HREI-MS), and tested against α-glucosidase, α-amylase, acetylcholinesterase, and butyrylcholinesterase inhibitory potentials. All analogues exhibited different inhibitory potentials, with IC50 values ranging between 7.5 ± 0.92 to 58.4 ± 0.07 μM (α-glucosidase), and 0.80 ± 0.05 to 15.30 ± 0.10 μM (α-amylase) as compared to the standard drug acarbose (IC50 = 38.45 ± 0.80 and 8.90 ± 0.10 μM). Out of fifteen analogues, nine showed an excellent inhibitory potency that was manyfold better than standard drugs. A slight increase or decrease in inhibition was observed due to substituents attached at imine site. In the case of α-amylase inhibition, two analogues such as 2 and 11, showed excellent inhibitory potential with IC50 values of 0.80 ± 0.05 and 0.90 ± 0.10 μM while all other analogues showed good potency. All analogues were also tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory potentials, and they showed good potentials ranging from 1.40 ± 0.20 to 16.20 ± 0.50 μM (AChE) and 3.20 ± 0.10 to 19.60 ± 0.20 μM (BuChE) as compared to the standard drug Donepezil (IC50 = 2.16 ± 0.12 μM and 4.5 ± 0.11 μM). In the case of AChE, analogue 3 is the most potent, and in the case of BuChE, analogue 9 is the most potent among the series. The structure-activity relationship was carried out, mainly associated with the nature, number, and position and the electron-donating and electron-withdrawing effects of the substituent(s) on the phenyl ring. The binding modes as well as binding free energy for α-glucosidase and α-amylase inhibitors were determined through docking studies.

In vitro and in silico analysis for elucidation of α-amylase and α-glucosidase: Synthesis, structural confirmation and drug likeness of benzothiazole derived thiazole base bis-Schiff base derivatives

In this study, we have synthesized S-substituted benzothiazole derived thiazole bearing bis-Schiff base derivatives (1–19) and characterized via different spectroscopic techniques including NMR and HR-EIMS and then screened against α-amylase and α-glycosidase. All the analogues show excellent inhibitory capability. Analogues 1 (IC50 = 3.18 ± 0.72 µM and 2.30 ± 1.80 µM) and 4 (IC50 = 1.40 ± 0.59 µM and 2.10 ± 0.78 µM) were found to be the strongest among the all in contrast with standard drug acarbose (IC50 = 4.30 ± 0.18 and 6.45 ± 1.84 µM) for α-amylase and α-glycosidase. Some derivatives show good potency against both the enzymes while few were found moderately potent. For all the molecules structure–activity relationship was carried to determine the decrease/increase in potency due to steric hindrance, bulky nature, position, type, size, quantity of the substituent/s on phenyl rings. Molecular docking and ADME analysis were carried out to signify the binding interactions of the most potent derivatives with the active site of enzymes.