Highly Potent and Selective Ectonucleoside Triphosphate Diphosphohydrolase (ENTPDase1, 2, 3 and 8) Inhibitors Having 2-substituted-7- trifluoromethyl-thiadiazolopyrimidones Scaffold

2020 ◽  
Vol 16 (5) ◽  
pp. 689-702 ◽  
Author(s):  
Saira Afzal ◽  
Sumera Zaib ◽  
Behzad Jafari ◽  
Peter Langer ◽  
Joanna Lecka ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Binding Pocket ◽  
Docking Studies ◽  
Extracellular Nucleotides ◽  
Nucleoside Triphosphate ◽  
Selective Inhibitors ◽  
Docking Analysis ◽  
Inhibitory Potential ◽  
Malachite Green Assay ◽  
Hydrolysis Of

Background: The ecto-nucleoside triphosphate diphosphohydrolases (NTPDases) terminate nucleotide signaling via the hydrolysis of extracellular nucleoside-5'-triphosphate and nucleoside- 5'-diphosphate, to nucleoside-5'-monophosphate and composed of eight Ca2+/Mg2+ dependent ectonucleotidases (NTPDase1-8). Extracellular nucleotides are involved in a variety of physiological mechanisms. However, they are rapidly inactivated by ectonucleotidases that are involved in the sequential removal of phosphate group from nucleotides with the release of inorganic phosphate and their respective nucleoside. Ectonucleoside triphosphate diphosphohydrolases (NTPDases) represent the key enzymes responsible for nucleotides hydrolysis and their overexpression has been related to certain pathological conditions. Therefore, the inhibitors of NTPDases are of particular importance in order to investigate their potential to treat various diseases e.g., cancer, ischemia and other disorders of the cardiovascular and immune system. Methods: Keeping in view the importance of NTPDase inhibitors, a series of thiadiazolopyrimidones were evaluated for their potential inhibitory activity towards NTPDases by the malachite green assay. Results: The results suggested that some of the compounds were found as non-selective inhibitors of isozyme of NTPDases, however, most of the compounds act as potent and selective inhibitors. In case of substituted amino derivatives (4c-m), the compounds 4m (IC50 = 1.13 ± 0.09 μM) and 4g (IC50 = 1.72 ± 0.08 μM) were found to be the most potent inhibitors of h-NTPDase1 and 2, respectively. Whereas, compound 4d showed the best inhibitory potential for both h-NTPDase3 (IC50 = 1.25 ± 0.06 μM) and h-NTPDase8 (0.21 ± 0.02 μM). Among 5a-t derivatives, compounds 5e (IC50 = 2.52 ± 0.15 μM), 5p (IC50 = 3.17 ± 0.05 μM), 5n (IC50 = 1.22 ± 0.06 μM) and 5b (IC50 = 0.35 ± 0.001 μM) were found to be the most potent inhibitors of h-NTPDase1, 2, 3 and 8, respectively. Interestingly, the inhibitory concentration values of above-mentioned inhibitors were several folds greater than suramin, a reference control. In order to determine the binding interactions, molecular docking studies of the most potent inhibitors were conducted into the homology models of NTPDases and the putative binding analysis further confirmed that selective and potent compounds bind deep inside the active pocket of the respective enzymes. Conclusions: The docking analysis proposed that the inhibitory activity correlates with the hydrogen bonds inside the binding pocket. Thus, these derivatives are of interest and may further be investigated for their importance in medicinal chemistry.

scholarly journals Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases

2020 ◽  
Vol 11 ◽  
Author(s):  
Saira Afzal ◽  
Mariya al-Rashida ◽  
Abdul Hameed ◽  
Julie Pelletier ◽  
Jean Sévigny ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Molecular Docking ◽  
Docking Studies ◽  
Nucleoside Triphosphate ◽  
Membrane Bound ◽  
Hydrolysis Of ◽  
Extracellular Environment ◽  
Micromolar Range

Ectonucleoside triphosphate diphosphohydrolases (NTPDases) are ectoenzymes that play an important role in the hydrolysis of nucleoside triphosphate and diphosphate to nucleoside monophosphate. NTPDase1, -2, -3 and -8 are the membrane bound members of this enzyme family that are responsible for regulating the levels of nucleotides in extracellular environment. However, the pathophysiological functions of these enzymes are not fully understood due to lack of potent and selective NTPDase inhibitors. Herein, a series of oxoindolin hydrazine carbothioamide derivatives is synthesized and screened for NTPDase inhibitory activity. Four compounds were identified as selective inhibitors of h-NTPDase1 having IC50 values in lower micromolar range, these include compounds 8b (IC50 = 0.29 ± 0.02 µM), 8e (IC50 = 0.15 ± 0.009 µM), 8f (IC50 = 0.24 ± 0.01 µM) and 8l (IC50 = 0.30 ± 0.03 µM). Similarly, compound 8k (IC50 = 0.16 ± 0.01 µM) was found to be a selective h-NTPDase2 inhibitor. In case of h-NTPDase3, most potent inhibitors were compounds 8c (IC50 = 0.19 ± 0.02 µM) and 8m (IC50 = 0.38 ± 0.03 µM). Since NTPDase3 has been reported to be associated with the regulation of insulin secretion, we evaluated our synthesized NTPDase3 inhibitors for their ability to stimulate insulin secretion in isolated mice islets. Promising results were obtained showing that compound 8m potently stimulated insulin secretion without affecting the NTPDase3 gene expression. Molecular docking studies of the most potent compounds were also carried out to rationalize binding site interactions. Hence, these compounds are useful tools to study the role of NTPDase3 in insulin secretion.

2-Mercapto Benzothiazole Derivatives: As Potential Leads for the Diabetic Management

2020 ◽  
Vol 16 (6) ◽  
pp. 826-840
Author(s):  
Saeed Ullah ◽  
Salma Mirza ◽  
Uzma Salar ◽  
Shafqat Hussain ◽  
Kulsoom Javaid ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Inhibitory Activity ◽  
Kinetic Studies ◽  
Binding Pocket ◽  
Docking Studies ◽  
Standard Drug ◽  
Dual Nature ◽  
Benzothiazole Derivatives ◽  
Glucosidase Inhibitors

Background: Results of our previous studies on antiglycation activity, and the noncytotoxicity of 2-mercapto benzothiazoles, encouraged us to further widen our investigation towards the identification of leads against diabetes mellitus. Methods: 33 derivatives of 2-mercapto benzothiazoles 1-33 were evaluated for in vitro α- glucosidase inhibitory activity. Mode of inhibition was deduced by kinetic studies. To predict the interactions of 2-mercapto benzothiazole derivatives 1-33 with the binding pocket of α-glucosidase enzyme, molecular docking studies were performed on the selected inhibitors. Results: Compounds 2-4, 6-7, 9-26, 28 and 30 showed many folds potent α-glucosidase inhibitory activity in the range of IC50 = 31.21-208.63 μM, as compared to the standard drug acarbose (IC50 = 875.75 ± 2.08 μM). It was important to note that except derivative 28, all other derivatives were also found previously to have antiglycating potential in the range of IC50 = 187.12-707.21 μM. Conclusion: A number of compounds were identified as dual nature as antiglycating agent and α- glucosidase inhibitors. These compounds may serve as potential lead candidates for the management of diabetes mellitus.

scholarly journals Synthesis, α-Amylase Inhibitory Activity and Molecular Docking Studies of 2,4-Thiazolidinedione Derivatives

2018 ◽  
Vol 5 (1) ◽  
pp. 134-144 ◽  
Author(s):  
Fawad Naeem ◽  
Humaira Nadeem ◽  
Aun Muhammad ◽  
Muhammad Ammar Zahid ◽  
Adil Saeed
Keyword(s):  
Acetic Acid ◽  
Inhibitory Activity ◽  
Docking Studies ◽  
Step Procedure ◽  
Anti Cancer ◽  
Active Site Cleft ◽  
Inhibitory Potential ◽  
Pharmacological Potential ◽  
Amylase Inhibitors ◽  
Derivatives Of

Introduction:2,4-Thiazolidinedione and its derivatives exhibit a variety of pharmacological activities including antidiabetic, antiviral, antifungal, anti-inflammatory, anti-cancer and aldose reductase inhibitory activities. Keeping in mind the pharmacological potential of 2,4-Thiazolidinedione derivatives as antidiabetic agents, seven arylidene derivatives of 2,4-thiazolidinedione1(a-g)and four corresponding acetic acid derivatives 2(a-d)have been synthesized by a three-step procedure.Methods:All the synthesized compounds were characterized by elemental analysis, FTIR,1HNMR, and13CNMR and further screened for their α-amylase inhibitory potential.Results:All the compounds1(a-g)and2(a-d)showed varying degree of α-amylase inhibition, especially compound1c(IC50= 6.59μg/ml),1d(IC50=2.03μg/ml) and1g(IC50= 3.14μg/ml) displayed significantly potent α-amylase inhibition as compared to the standard acarbose (IC50= 8.26μg/ml). None of the acetic acid derivatives of 5-arylidene-2,4-thiazolidinedione showed prominent inhibitory activity. Docking results indicated that the best binding conformation was found inside the active site cleft of enzyme responsible for hydrolysis of carbohydrates.Conclusion:Therefore, it can be concluded that 2,4-thiazolidinedione derivatives can be used as effective lead molecules for the development of α-amylase inhibitors for the management of diabetes.

scholarly journals Antidiabetic and Antioxidant Potential of GancidinW from Streptomyces Paradoxus VITALK03

2017 ◽  
Vol 5 (1) ◽  
pp. 31-42
Author(s):  
Lokesh Ravi ◽  
Adhithya Ragunathan ◽  
Kannabiran Krishnan
Keyword(s):  
Glucose Uptake ◽  
Inhibitory Activity ◽  
Docking Studies ◽  
Antioxidant Potential ◽  
Yeast Cells ◽  
Antidiabetic Agent ◽  
Dpph Assay ◽  
Binding Interaction ◽  
Docking Analysis ◽  
Free Binding Energy

Background:The aim of the present study was to analyse the antidiabetic and antioxidant potential of GancidinW (GW) extracted fromStreptomyces paradoxusVITALK03.Materials and Methods:Antidiabetic potential of GW was evaluated by assay of α-amylase and α-glucosidase inhibitory activity; haemoglobin glycosylation and yeast glucose uptake. The antioxidant potential of GW was assessed by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay, 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation decolorization assay and superoxide assay. The inhibition of α-amylase and α-glucosidase by GW was also studied byin Silicomolecular docking analysis.Results:GW (1mg/ml) showed 69.32% of α-amylase and 54.04% of α-glucosidase inhibitory activity. GW (1mg/ml) prevented haemoglobin glycosylation up to 30.92% and the glucose uptake by yeast cells was increased up to 64.38%. The binding interaction GW with α-amylase showed the least free binding energy of -6.09Kcal/mol and -7.53Kcal/mol with α-glucosidase by docking studies. GW also demonstrated moderate antioxidant activity in all the antioxidant assays performed.Conclusion:The results of this study suggests that the antidiabetic and antioxidant potential of GW can be probed further to develop GW as effective antidiabetic agent.

scholarly journals Thiazole Based Carbohydrazide Derivatives as α-Amylase Inhibitor and Their Molecular Docking Study

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Muhammad Taha ◽  
Maryam Irshad ◽  
Syahrul Imran ◽  
Fazal Rahim ◽  
Manikandan Selvaraj ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Docking Study ◽  
Docking Studies ◽  
Antidiabetic Agent ◽  
Molecular Docking Study ◽  
Binding Interaction ◽  
Structure Activity ◽  
Inhibitory Potential ◽  
Amylase Inhibitors

In this study we are going to present thiazole based carbohydrazide in search of potent antidiabetic agent as α-amylase inhibitors. Thiazole based carbohydrazide derivatives 1-25 have been synthesized, characterized by 1HNMR, 13CNMR, and EI-MS, and evaluated for α-amylase inhibition. Except compound 11 all analogs showed α-amylase inhibitory activity with IC50 values from 1.709 ± 0.12 to 3.049 ± 0.25 μM against the standard acarbose (IC50 = 1.637 ± 0.153 μM). Compounds 1, 10, 14, and 20 exhibited outstanding inhibitory potential with IC50 value 1.763 ± 0.03, 1.747 ± 0.20, 1.709 ± 0.12, and 1.948 ± 0.23 μM, respectively, compared with the standard acarbose. Structure activity relationships have been established for the active compounds. To get an idea about the binding interaction of the compounds, molecular docking studies were done.

scholarly journals Bioactive Aporphine Alkaloids from the Roots of Artabotrys spinosus: Cholinesterase Inhibitory Activity and Molecular Docking Studies

2018 ◽  
Vol 13 (10) ◽  
pp. 1934578X1801301
Author(s):  
Jirapast Sichaem ◽  
Santi Tip-pyang ◽  
Kiattisak Lugsanangarm
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Mixed Mode ◽  
Docking Studies ◽  
Experimental Results ◽  
Docking Analysis ◽  
Molecular Docking Studies ◽  
Cholinesterase Inhibitory Activity ◽  
Inhibitory Activities ◽  
Molecular Docking Analysis

Six aporphine alkaloids (1–6) were isolated from Artabotrys spinosus roots based on bioassay-guided fraction and chromatographic methods. All isolated alkaloids were evaluated for their cholinesterase (ChEs) inhibitory activities, in which compounds 4 and 6 exhibited the highest activity toward butyrylcholinesterase (BChE) and acetylcholinesterase (AChE), respectively. The Lineweaver-Burk plots suggested that 4 and 6 were mixed mode inhibitors toward BChE and AChE enzymes, respectively. In addition, the experimental results were also confirmed by molecular docking analysis. This information can help in designing a new inhibitor in the class of aporphine alkaloids in against Alzheimer's disease.

scholarly journals Anti-Diabetic Activity of Whey Proteins

2020 ◽  
Vol 50 (2) ◽  
pp. 306-318
Author(s):  
E. Agarkova ◽  
Ksenia A Ryazantseva ◽  
A. Kruchinin
Keyword(s):  
Inhibitory Activity ◽  
Whey Proteins ◽  
Biologically Active ◽  
Cottage Cheese ◽  
Processing Technologies ◽  
Dpp Iv ◽  
Ic50 Value ◽  
Inhibitory Potential ◽  
Β Lactoglobulin ◽  
Hydrolysis Of

Absract. Introduction. With the advent of membrane filtration technologies, milk whey stopped being a “by-product” of cheese, cottage cheese, and casein production. The combination of various whey-processing technologies, e.g. enzymatic hydrolysis and membrane fractionation, made it possible to obtain concentrates, isolates, and hydrolysates of whey proteins with various biologically active effects. Study objects and methods. The article features research results of Russian and foreign scientific teams in the development of functional antidiabetic ingredients from hydrolyzed proteins of milk and whey. Results and discussion. According to foreign studies, Ile-Pro-Ile (diprotin A) with an IC50 value of 4.7 μM is one of the most effective low molecular mass peptides with an inhibitory potential against DPP-IV. Various studies of trypsin hydrolysis of β-lactoglobulin described the production of IPAVF peptide fragment with the most potent inhibitory activity of DPP-IV (IC50 = 44.7 μM). Other studies featured pepsin-treated lactoglobulin production of fragments LKPTPEGDL and LKPTPEGDLEIL with inhibitory activity DPP-IV IC50 = 45 and 57 μM, respectively. A number of studies described similar fragments obtained by the sequential action of the enzyme preparation Neutrase 0.8 LTM on β-lactoglobulin, followed by pepsin hydrolysis. As for the hydrolysis of α-lactalbumin with pepsin, scientists identified peptides WLAHKALCSEKLDQ, LAHKALCSEKL, and TKCEVFRE. They revealed a high inhibitory potential against DPP-IV (IC50 = 141, 165, and 166 μM, respectively). Tryptic hydrolysates of bovine β-lactoglobulin proved to be able to inhibit DPP-IV in vitro (IC50 of 210 μM). Peptide VAGTWY was the major compound responsible for this effect, displaying an IC50 of 174 μM. In other research, tryptic hydrolysate inhibited DPP-IV with an IC50 value of 1.6 mg/mL, also demonstrating antioxidant and ACE-inhibitory activities. This hydrolysate became source of VAGTWY, the most potent DPP-IV inhibitor (IC50 of 74.9 μM). Conclusion. An analysis of Russian and foreign studies proved that milk protein hydrolysis has a great potential for antidiabetic additives used in the treatment of type II diabetes. This are requires further research in order to define the safety of biologically active peptides.

New pyrimidines and triazolopyrimidines as antiproliferative and antioxidants with cyclooxygenase-1/2 inhibitory potential

2019 ◽  
Vol 11 (13) ◽  
pp. 1583-1603
Author(s):  
Ashraf M Omar ◽  
Heba A Abd El Razik ◽  
Aly A Hazzaa ◽  
Maryam AZ El-Attar ◽  
Maha A El Demellawy ◽  
...  
Keyword(s):  
Free Radicals ◽  
Inhibitory Activity ◽  
Docking Studies ◽  
Cyclooxygenase 1 ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Cox 2 ◽  
Inhibitory Potential ◽  
Cox 1 ◽  
Mcf 7

Aim: Cyclooxygenase-2 (COX-2) inhibition and scavenging-free radicals are important targets in cancer treatment. Materials & methods: Sulfanylpyrimidines and triazolopyrimidines were synthesized and evaluated as anticancer and antioxidant COX-1/2 inhibitors. Results: Compound 7 showed the same growth inhibitory activity as 5-fluorouracil against MCF-7. Compound 6f displayed broad-spectrum anticancer activity against the four tested cancer cell lines. Compounds 5b, 6a, 6c, 6d and 8 were found to be more active antioxidants than trolox. Compounds 6a, 6c, 6f and 8 revealed high COX-2 inhibitory activity and selectivity, which was confirmed by docking studies. Conclusion: Compound 6f could be considered as promising anticancer and antioxidant structural lead with COX-2 inhibition that deserve further derivatization and investigation.

Synthesis, In vitro α-Glucosidase Inhibitory Potential and Molecular Docking Studies of 2-Amino-1,3,4-Oxadiazole Derivatives

2020 ◽  
Vol 16 (6) ◽  
pp. 724-734 ◽  
Author(s):  
Hayat Ullah ◽  
Fazal Rahim ◽  
Muhammad Taha ◽  
Raffaqat Hussain ◽  
Abdul Wadood ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Docking Studies ◽  
Spectroscopic Techniques ◽  
Ongoing Research ◽  
Molecular Docking Studies ◽  
Ic50 Value ◽  
Oxadiazole Derivatives ◽  
Inhibitory Potential ◽  
Synthetic Derivatives

Background: In the recent past, we have synthesized and reported different derivatives of oxadiazoles as potential α-glucosidase inhibitors, keeping in mind, the pharmacological aspects of oxadiazole moiety and in continuation of our ongoing research on the chemistry and bioactivity of new heterocyclic compounds. Methods: 1,3,4-Oxadiazole derivatives (1-14) have been synthesized and characterized by different spectroscopic techniques such as 1H-, 13C-NMR and HREI-MS. Result: The synthetic derivatives were screened for α-glucosidase inhibitory potential. All compounds exhibited good inhibitory activity with IC50 values ranging between 0.80 ± 0.1 to 45.1 ± 1.7 μM in comparison with the standard acarbose having IC50 value 38.45 ± 0.80 μM. Conclusion: Thirteen compounds 1-6 and 8-14 showed potential inhibitory activity as compared to the standard acarbose having IC50 value 38.45 ± 0.80 μM, however, only one compound 7 (IC50 = 45.1 ± 1.7 μM) was found to be less active. Compound 14 (IC50 = 0.80 ± 0.1 μM) showed promising inhibitory activity among all synthetic derivatives. Molecular docking studies were also conducted for the active compounds to understand the ligand-enzyme binding interactions.

Substituted 6,7-dimethoxy-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole- 3-1,1-dioxide Derivatives with Antimicrobial Activity and Docking Assisted Prediction of the Mechanism of their Antibacterial and Antifungal Properties

2020 ◽  
Vol 20 (29) ◽  
pp. 2681-2691
Author(s):  
Athina Geronikaki ◽  
Victor Kartsev ◽  
Phaedra Eleftheriou ◽  
Anthi Petrou ◽  
Jasmina Glamočlija ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Antifungal Activity ◽  
Drug Targets ◽  
Bacterial Species ◽  
Pharmaceutical Research ◽  
Docking Studies ◽  
Fungal Species ◽  
Docking Analysis ◽  
E Coli ◽  
Antibacterial And Antifungal

Background: Although a great number of the targets of antimicrobial therapy have been achieved, it remains among the first fields of pharmaceutical research, mainly because of the development of resistant strains. Docking analysis may be an important tool in the research for the development of more effective agents against specific drug targets or multi-target agents 1-3. Methods: In the present study, based on docking analysis, ten tetrahydrothiazolo[2,3-a]isoindole derivatives were chosen for the evaluation of the antimicrobial activity. Results: All compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species being, in some cases, more potent than ampicillin and streptomycin against all species. The most sensitive bacteria appeared to be S. aureus and En. Cloacae, while M. flavus, E. coli and P. aeruginosa were the most resistant ones. The compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited good antifungal activity better than reference drugs bifonazole (1.4 – 41 folds) and ketoconazole (1.1 – 406 folds) against all fungal species. In order to elucidate the mechanism of action, docking studies on different antimicrobial targets were performed. Conclusion: According to docking analysis, the antifungal activity can be explained by the inhibition of the CYP51 enzyme for most compounds with a better correlation of the results obtained for the P.v.c. strain (linear regression between estimated binding Energy and log(1/MIC) with R 2 =0.867 and p=0.000091 or R 2 = 0.924, p= 0.000036, when compound 3 is excluded.

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