Synthesis, α-glucosidase inhibitory activity and in silico study of tris-indole hybrid scaffold with oxadiazole ring: As potential leads for the management of type-II diabetes mellitus (original) (raw)
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Oxindole based oxadiazole hybrid analogs: Novel α-glucosidase inhibitors
Bioorganic chemistry, 2017
Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. Beside these α-glucosidase inhibitors has been also used as anti-obesity and anti-viral drugs. Keeping in view the greater importance of α-glucosidase inhibitors here in this study we are presenting oxindole based oxadiazoles hybrid analogs (1-20) synthesis, characterized by different spectroscopic techniques including 1H NMR and EI-MS and their α-glucosidase inhibitory activity. All compounds were found potent inhibitors for the enzyme with IC50 values ranging between 1.25 ± 0.05 and 268.36 ± 4.22 µM when compared with the standard drug acarbose having IC50 value 895.09 ± 2.04 µM. Our study identifies novel series of potent α-glucosidase inhibitors and further investigation on this may led to the lead compounds. A structure activity relationship has been established for all compounds. The interactions of the active compounds and enzyme active site were established ...
Bioorganic chemistry, 2018
Current study is based on the sequential conversion of indolyl butanoic acid (1) into ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4) by adopting chemical transformations. In a parallel series of reactions, 2-bromo-N-phenyl/arylacetamides (7a-l) were synthesized by reacting different amines derivatives (5a-l) with 2-bromoacetyl bromide (6) to serve as electrophile. Then, the synthesized electrophiles (7a-l) were treated with nucleophilic 1,3,4-oxadiazole-2-thiol analog (4) to afford a range of N-substituted derivatives (8a-l). The structural confirmation of all the synthetic compounds was carried out by IR, H-, C NMR, EI-MS, and CHN analysis data. All synthesized molecules (8a-l) were tested for their antidiabetic potential via inhibition of the α-glucosidase enzyme followed by their in silico study. Their cytotoxicity profile was also ascertained via hemolytic activity and all of them possessed very low cytotoxicity. Compounds 8h a...
Bioorganic chemistry, 2018
A series of triarylimidazoles substituted with 2-arylindoles (4a-4j) were prepared and evaluated for their in vitro α-Glucosidase inhibition. α-Glucosidase inhibition assay displayed a new class of highly potent agents The new compounds showed significant α-glucosidase inhibitory activity as compared to the standard inhibitor acrabose. Structures of synthesized compounds were determined by using Mass spectrometry FT-IR,H NMR andC NMR.
Scientific Reports
The control of postprandial hyperglycemia is an important target in the treatment of type 2 diabetes mellitus (T2DM). As a result, targeting α-glucosidase as the most important enzyme in the breakdown of carbohydrates to glucose that leads to an increase in postprandial hyperglycemia is one of the treatment processes of T2DM. In the present work, a new class of benzimidazole-Schiff base hybrids 8a–p has been developed based on the potent reported α-glucosidase inhibitors. These compounds were synthesized by sample recantations, characterized by 1H-NMR, 13C-NMR, FT-IR, and CHNS elemental analysis, and evaluated against α-glucosidase. All new compounds, with the exception of inactive compound 8g, showed excellent inhibitory activities (60.1 ± 3.6–287.1 ± 7.4 µM) in comparison to acarbose as the positive control (750.0 ± 10.5). Kinetic study of the most potent compound 8p showed a competitive type of inhibition (Ki value = 60 µM). In silico induced fit docking and molecular dynamics st...
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.
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
Molecules
β-glucuronidase is a lysosomal glycosidase enzyme which catalyzes the extracellular matrix of cancer and normal cells and the glycosaminoglycans of the cell membrane, which is important for cancer cell proliferation, invasion, and metastasis. Liver cancer, colon carcinoma, and neoplasm bladder are triggered by the increase of the level of β-glucuronidase activity. The most valuable structures are indole and oxadiazole which has gain immense attention because of its pharmacological behavior and display many biological properties. Twenty-two (1–22) analogs of indole based oxadiazole were synthesized and screened for their inhibitory potential against β-glucuronidase. Majority of the compounds showed potent inhibitory potential with IC50 values ranging between 0.9 ± 0.01 to 46.4 ± 0.9 µM, under positive control of standard drug d-saccharic acid 1,4 lactone (IC50 = 48.1 ± 1.2 µM). Structural activity relationship (SAR) has been established for all synthesized compounds. To shed light on...
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...
A novel series of multifunctional benzimidazoles has been reported as potent inhibitors of α-glucosidase. The procedure relies on the synthesis of 5-amino-1H-benzo[d]imidazole-2-thiol 5 via the multistep reaction through 2-nitroaniline 1, benzene-1,2-diamine 2, 1H-benzo[d]imidazole-2-thiol 3, and 5-nitro-1H-benzo[d]imidazole-2-thiol 4. Further treatment of 5 with aromatic aldehydes 6a−m provided access to the target 5-(arylideneamino)-1H-benzo[d]imidazole-2-thiols 7a−m. The results of the bioactivity assessment revealed all the compounds as excellent inhibitors of the enzyme (IC 50 range: 0.64 ± 0.05 μM to 343.10 ± 1.62 μM) than acarbose (873.34 ± 1.21). Among them, 7i was the most active inhibitor (IC 50 : 0.64 ± 0.05 μM) followed by 7d (