Coumarin linked thiazole derivatives as potential α-Glucosidase inhibitors to treat Diabetes Mellitus (original) (raw)
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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.
Bioorganic chemistry, 2018
α-Glucosidase is a catabolic enzyme that regulates the body's plasma glucose levels by providing energy sources to maintain healthy functioning. 2-Amino-thiadiazole (1-13) and 2-amino-thiadiazole based Schiff bases (14-22) were synthesized, characterized byH NMR and HREI-MS and screened for α-glucosidase inhibitory activity. All twenty-two (22) analogs exhibit varied degree of α-glucosidase inhibitory potential with ICvalues ranging between 2.30 ± 0.1 to 38.30 ± 0.7 μM, when compare with standard drug acarbose having ICvalue of 39.60 ± 0.70 μM. Among the series eight derivatives 1, 2, 6, 7, 14, 17, 19 and 20 showed outstanding α-glucosidase inhibitory potential with ICvalues of 3.30 ± 0.1, 5.80 ± 0.2, 2.30 ± 0.1, 2.70 ± 0.1, 2.30 ± 0.1, 5.50 ± 0.1, 4.70 ± 0.2, and 5.50 ± 0.2 μM respectively, which is many fold better than the standard drug acarbose. The remaining analogs showed good to excellent α-glucosidase inhibition. Structure activity relationship has been established for a...
Bioorganic Chemistry
A series of thiazole derivatives 1-21 were prepared, characterized by EI-MS and (1)H NMR and evaluated for α-glucosidase inhibitory potential. All twenty one derivatives showed good α-glucosidase inhibitory activity with IC50 value ranging between 18.23±0.03 and 424.41±0.94μM when compared with the standard acarbose (IC50, 38.25±0.12μM). Compound (8) (IC50, 18.23±0.03μM) and compound (7) (IC50=36.75±0.05μM) exhibited outstanding inhibitory potential much better than the standard acarbose (IC50, 38.25±0.12μM). All other analogs also showed good to moderate enzyme inhibition. Molecular docking studies were carried out in order to find the binding affinity of thiazole derivatives with enzyme. Studies showed these thiazole analogs as a new class of α-glucosidase inhibitors. Copyright © 2015. Published by Elsevier Inc.
Bioorganic Chemistry, 2016
A novel series of chromone-isatin derivatives 6a-6p were designed, synthesized and characterized by 1 H NMR, 13 C NMR and HRMS. These novel synthetic compounds were evaluated for inhibitory activity against yeast α-glucosidase enzyme. The results of biological test have shown that all tested compounds exhibited excellent to potent inhibitory activity in the range of IC 50 = 3.18 ± 0.12-16.59 ± 0.17 µM as compared to the standard drug acarbose (IC 50 = 817.38 ± 6.27 µM). Compound 6j (IC 50 = 3.18 ± 0.12 µM) with a hydroxyl group at the 7-position of chromone and a 4-bromobenzyl group at the N1-positions of isatin, was found to be the most active compound among the series. Furthermore, molecular docking study was performed to help understand binding interactions of the most active analogs with α-glucosidase enzyme. These results indicated that this class of compounds had potential for the development of anti-diabetic agents.
ACS Omega, 2024
Diabetes is an emerging disorder in the world and is caused due to the imbalance of insulin production as well as serious effects on the body. In search of a better treatment for diabetes, we designed a novel class of 1,3,4-thiadiazole-bearing Schiff base analogues and assessed them for the α-glucosidase enzyme. In the series (1−12), compounds are synthesized and 3 analogues showed excellent inhibitory activity against αglucosidase enzymes in the range of IC 50 values of 18.10 ± 0.20 to 1.10 ± 0.10 μM. In this series, analogues 4, 8, and 9 show remarkable inhibition profile IC 50 2.20 ± 0.10, 1.10 ± 0.10, and 1.30 ± 0.10 μM by using acarbose as a standard, whose IC 50 is 11.50 ± 0.30 μM. The structure of the synthesized compounds was confirmed through various spectroscopic techniques, such as NMR and HREI-MS. Additionally, molecular docking, pharmacokinetics, cytotoxic evaluation, and density functional theory study were performed to investigate their behavior.
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.
Bioorganic chemistry, 2018
Diabetes mellitus (DM), a chronic multifarious metabolic disorder resulting from impaired glucose homeostasis has become one of the most challenging diseases with severe life threat to public health. The inhibition of α-glucosidase, a key carbohydrate hydrolyzing enzyme, could serve as one of the effective methodology in both preventing and treating diabetes through controlling the postprandial glucose levels and suppressing postprandial hyperglycemia. In this context, three series of diamine-bridged bis-coumarinyl oxadiazole conjugates were designed and synthesized by one-pot multi-component methodology. The synthesized conjugates (4a-j, 5a-j, 6a-j) were evaluated as potential inhibitors of glucosidases. Compound 6f containing 4,4'-oxydianiline linker was identified as the lead and selective inhibitor of α-glucosidase enzyme with an ICvalue of 0.07 ± 0.001 μM (acarbose: IC = 38.2 ± 0.12 μM). This inhibition efficacy was ∼545-fold higher compared to the standard drug. Compound 6...
Bioorganic chemistry, 2017
Discovery of α-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of type-II diabetes mellitus and the other carbohydrate mediated disease. In continuation of our drug discovery research on potential antidiabetic agents, we synthesized novel tris-indole-oxadiazole hybrid analogs (1-21), structurally characterized by various spectroscopic techniques such as (1)H NMR, EI-MS, and (13)C NMR. Elemental analysis was found in agreement with the calculated values. All compounds were evaluated for α-glucosidase inhibiting potential and showed potent inhibitory activity in the range of IC50=2.00±0.01-292.40±3.16μM as compared to standard acarbose (IC50=895.09±2.04µM). The pharmacokinetic predictions of tris-indole series using descriptor properties showed that almost all compounds in this series indicate the drug aptness. Detailed binding mode analyses with docking simulation was also carried out which showed that the inhibitors can be stab...
Molecules
Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good ...
Scientific Reports, 2022
In this study, 18 novel quinoline-based-benzo[d]imidazole derivatives were synthesized and screened for their α-glucosidase inhibitory potential. All compounds in the series except 9q showed a significant α-glucosidase inhibition with IC 50 values in the range of 3.2 ± 0.3-185.0 ± 0.3 µM, as compared to the standard drug acarbose (IC 50 = 750.0 ± 5.0 µM). A kinetic study indicated that compound 9d as the most potent derivative against α-glucosidase was a competitive type inhibitor. Furthermore, the molecular docking study revealed the effective binding interactions of 9d with the active site of the α-glucosidase enzyme. The results indicate that the designed compounds have the potential to be further studied as new anti-diabetic agents. Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia, with the disorder in carbohydrate, fat, and protein metabolism in the body 1. DM is known as an important public health threat with around 450 million cases worldwide in 2019. This number is expected to rise to 700 million by 2045 worldwide confirming further action is required in this field 2,3. Long-term DM can increase the risk of various health complications including blindness, renal failure, foot amputation, as well as cardiovascular, retinopathy, and renal diseases 4. Type 2 diabetes mellitus (T2DM) with around 90% of all cases is categorized as a major sub-type of DM. It was considered that glycemic control could be effective prevention and treatment for T2DM 5-7. α-Glucosidase (EC 3.2.1.20) is a catalytic hydrolase enzyme present on the brush border of the small intestine which hydrolyzes oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides at their non-reducing ends 7-10. The produced monosaccharides especially glucose enter the bloodstream, resulting in postprandial hyperglycemia thus causing diabetes 11-13. Therefore, the inhibition of α-glucosidase might reduce carbohydrate digestion, delay glucose uptake, and consequently, decrease blood sugar levels 14,15. The α-glucosidase enzyme can be inhibited by acarbose, voglibose, and miglitol with sub-optimal efficacy 16. Also, long-term administration of mentioned inhibitor may cause several side effects, such as abdominal pain, diarrhea, and flatulence. As a result, a need of effective inhibitors to target α-glucosidase is highly needed 17-19. In the last few decades, different synthetic small molecules including benzo[d]imidazole 20 , isatin 21 benzo[b] thiophene 22 pyrimidine 23 , xanthone 24 , chromene 6 , azole 18,25 against α-glucosidase attracted increasing attention.