Evaluation of α-glucosidase inhibiting potentials with docking calculations of synthesized arylidene-pyrazolones (original) (raw)
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Scientific Reports, 2021
In this work, new derivatives of biphenyl pyrazole-benzofuran hybrids were designed, synthesized and evaluated in vitro through enzymatic assay for inhibitory effect against α-glucosidase activity. Newly identified inhibitors were found to be four to eighteen folds more active with IC50 values in the range of 40.6 ± 0.2–164.3 ± 1.8 µM, as compared to the standard drug acarbose (IC50 = 750.0 ± 10.0 μM). Limited Structure-activity relationship was established. A kinetic binding study indicated that most active compound 8e acted as the competitive inhibitors of α-glucosidase with Ki = 38 μM. Molecular docking has also been performed to find the interaction modes responsible for the desired inhibitory activity. As expected, all pharmacophoric features, used in the design of the hybrid, are involved in the interaction with the active site of the enzyme. In addition, molecular dynamic simulations showed compound 8e oriented vertically into the active site from mouth to the bottom and stab...
Chemical Papers, 2019
One of the therapeutic approaches in the management of type 2 diabetes is delaying the glucose absorption through α-glucosidase enzyme inhibition, which can reduce the occurrence of postprandial hyperglycemia. Based on this thought, a series of novel chloro-substituted 2-(2-methyl-1-phenyl-1H-pyrrol-3-yl)-2-oxo-N-(pyridin-3-yl) acetamide derivatives 5a-i were synthesized and their α-glucosidase inhibitory activities were evaluated. All the synthesized compounds have shown moderate to excellent in vitro α-glucosidase inhibitory activity with IC 50 values in the range of 111-673 µM) as compared to acarbose, the standard drug (750 ± 9 µM). Compound 5e (111 ± 12 µM), among the series, was the most potent inhibitor of α-glucosidase in a competitive mode of action based on the kinetic study. The molecular docking study of compounds 5e and 5a revealed that they have a lower free binding energy (− 4.27 kcal/mol and − 3.17 kcal/mol, respectively) than acarbose (− 2.47 kcal/mol), which indicates that the target compound binds more easily to the enzyme than acarbose does. The outcomes from the molecular docking studies supported the results obtained from the in vitro assay. In conclusion, the overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel α-glucosidase inhibitors to manage postprandial hyperglycemia incidence.
Bioorganic Chemistry, 2019
Herein, substituted imidazole-pyrazole hybrids (2a-2n) were prepared via a multi component reaction employing pyrazole-4-carbaldehydes (1a-1d), ammonium acetate, benzil and arylamines as reactants. All the new compounds were characterized through their spectral and elemental analyses. Further these compounds were tested against α-glucosidase enzyme. The compounds 2k, 2l and 2n possessed good inhibition potencies, however, compounds 2f (IC 50 value: 25.19±0.004 μM) and 2m (IC 50 value: 33.62±0.03 μM) were the most effective compounds of the series. Furthermore, molecular docking helped to understand the binding interactions of 2f and 2m with the understudy yeast's α-glucosidase enzyme.
BMC Chemistry, 2019
Diabetes is an emerging metabolic disorder. α-Glucosidase inhibitors, such as acarbose, delay the hydrolysis of carbohydrates by interfering with the digestive enzymes. This action decreases the glucose absorption and the postprandial glucose level. We have synthesized 25 tricyclic 2-phenoxypyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones hybrids and evaluated their α-glucosidase inhibitory activity. Compounds 6h and 6d have shown stronger activity than that of acarbose. Compound 6h exhibited the highest inhibition with an IC 50 of 104.07 µM. Molecular modelling studies revealed that compound 6h inhibits α-glucosidase due to the formation of a stable ligand-αglucosidase complex and extra hydrogen bond interactions, and directed in the binding site by Trp329.25 tricyclic 2-phenoxypyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones hybrids have been synthesized and evaluated their α-glucosidase inhibitory activity. Compounds 6h have shown stronger activity than that of acarbose
European Journal of Medicinal Chemistry, 2016
3-Thiazolylcoumarin derivatives 1-14 were synthesized via one-pot two step reactions, and screened for in vitro α-glucosidase inhibitory activity. All compounds showed inhibitory activity in the range of IC 50 = 0.12 ± 0.01-16.20 ± 0.23 µM as compared to standard acarbose (IC 50 = 38.25 ± 0.12 µM), and also found to be nontoxic. Molecular docking study was carried out in order to establish the structure-activity relationship (SAR) which demonstrated that electron rich centers at one and electron withdrawing centers at the other end of the molecules showed strong inhibitory activity. All the synthesized compounds were characterized by spectroscopic techniques such as EI-MS, HREI-MS, 1 H-NMR and 13 C-NMR. CHN analysis was also performed.
Journal of The Taiwan Institute of Chemical Engineers, 2017
α-Glucosidase inhibitors have extensively been exploited for the effective management of type 2 diabetes and associated complications by significantly reducing the postprandial increase in glucose and plasma insulin levels. In this endeavour, we designed and synthesized a new series of coumarinyl iminothiazolidinone hybrid compounds (6a-o) using a one-pot multi-component approach. The hybrid structures were accessed in good chemical yields. The synthesized compounds were tested for their glucosidase inhibitory efficacy using acarbose as a standard inhibitor (IC 50 = 38.2 ± 0.12 μM). In-vitro analysis of the hybrid molecules identified several potential leads for the development of potent glucosidase inhibitors with IC 50 values in the range of 0.09-0.92 μM with compound 6g being the most potent drug candidate (IC 50 = 0.09 ± 0.001 μM). Furthermore, compound 6f was identified as the lead inhibitor against maltaseglucoamylase with comparable inhibitory efficacy to acarbose with an IC 50 value of 0.07 ± 0.016 μM. Binding interactions of potent compounds with the key residues in the active site of the glucosidase enzyme were revealed by molecular docking analysis. In summary, these new structural leads based on the hybrid pharmacophores could be developed as potential inhibitors of α-glucosidase for treating postprandial hyperglycemia.
PLOS ONE
High throughput screening of synthetic compounds against vital enzymes is the way forward for the determination of potent enzyme inhibitors. In-vitro high throughput library screening of 258 synthetic compounds (comp. 1–258), was performed against α-glucosidase. The active compounds out of this library were investigated for their mode of inhibition and binding affinities towards α-glucosidase through kinetics as well as molecular docking studies. Out of all the compounds selected for this study, 63 compounds were found active within the IC50 range of 3.2 μM to 50.0 μM. The most potent inhibitor of α-glucosidase out of this library was the derivative of an oxadiazole (comp. 25). It showed the IC50 value of 3.23 ± 0.8 μM. Other highly active compounds were the derivatives of ethyl-thio benzimidazolyl acetohydrazide with IC50 values of 6.1 ± 0.5 μM (comp. 228), 6.84 ± 1.3 μM (comp. 212), 7.34 ± 0.3 μM (comp. 230) and 8.93 ± 1.0 μM (comp. 210). For comparison, the standard (acarbose) sh...
World Journal of Biology Pharmacy and Health Sciences
The primary goal of this study is to bring the elevated blood sugars down to a normal range, both to improve symptoms of diabetes as well as to prevent or delay diabetic complications. Achieving this goal requires a comprehensive, coordinated, patient-centered approach on the part of the healthcare system. The potions extracted from the generated Docking models are statistically aesthetic and provide enough assumptions about the character as well as the nature of substitutions favourable to boost the biological efficiency of novel analogous. The potion provided by these computational studies helps to derive an impactful path to design more potent antihyperglycemic counterparts of dihydro-pyrazole.
Bioorganic chemistry, 2016
Twenty derivatives of 5-aryl-2-(6'-nitrobenzofuran-2'-yl)-1,3,4-oxadiazoles (1-20) were synthesized and evaluated for their α-glucosidase inhibitory activities. Compounds containing hydroxyl and halogens (1-6, and 8-18) were found to be five to seventy folds more active with IC50 values in the range of 12.75±0.10-162.05±1.65μM, in comparison with the standard drug, acarbose (IC50=856.45±5.60μM). Current study explores the α-glucosidase inhibition of a hybrid class of compounds of oxadiazole and benzofurans. These findings may invite researchers to work in the area of treatment of hyperglycemia. Docking studies showed that most compounds are interacting with important amino acids Glu 276, Asp 214 and Phe 177 through hydrogen bonds and arene-arene interaction.