Molecular modelling studies on thiazole-based α-Glucosidase Inhibitor using docking and CoMFA, CoMSIA and HQSAR

2020 ◽  
Vol 17 ◽  
Author(s):  
Deshbandhu Joshi ◽  
Shourya Yadav ◽  
Rajesh Sharma ◽  
Mitrunjaya Pandya ◽  
Raghvendra Singh Bhadauria
Keyword(s):  
Correlation Coefficient ◽  
Training Set ◽  
Glucosidase Inhibitors ◽  
Biological Dataset ◽  
Donor And Acceptor ◽  
Molecular Modelling Studies ◽  
Ic50 Values ◽  
Modelling Studies ◽  
Standard Error Estimation ◽  
Leave One Out

Aims and Objective: The biological dataset was retrieved from two series of α-glucosidase inhibitors synthesized by Rahim et al. and Taha et al. and consisted of a total 46 (forty-six) α-glucosidase inhibitors. Methods: The α-glucosidase inhibitory IC50 values (µM; performed against α-glucosidase from Saccharomyces cerevisiae) were converted into negative logarithmic units (pIC50). The CoMFA and CoMSIA models were created utilizing 37 as the training set and externally validated utilizing 9 as a test set. The CoMFA models MMFF94 were generated and ranging from 3.4661 to 5.2749 using leave-one-out PLS analysis cross-validated correlation coefficient q2 0.787 a high non-crossvalidated correlation coefficient r2 0.819 with a low standard error estimation (SEE) 0.041, F value 1316.074 and r2pred 0.996. Results: The steric and electrostatic fields contributions were 0.507 and 0.493, respectively. The CoMSIA model q2 0.805, r 2 0.833 was attained, (SEE) 0.065, F value 520.302 and r2pred 0.990. Contribution of steric, electrostatic, hydrophobic, donor and acceptor fields were 0.151, 0.268, 0.223, 0.234, 0.124 respectively. Conclusion: The HQSAR model of training set exhibits significant cross-validated correlation coefficient q2 0.800 and noncross-validated correlation coefficient r2 0.943.

scholarly journals Prediction of the Toxicity of Binary Mixtures by QSAR Approach Using the Hypothetical Descriptors

2018 ◽  
Vol 19 (11) ◽  
pp. 3423 ◽  
Author(s):  
Ting Wang ◽  
Lili Tang ◽  
Feng Luan ◽  
M. Natália D. S. Cordeiro
Keyword(s):  
Correlation Coefficient ◽  
Binary Mixtures ◽  
Quantitative Structure Activity Relationship ◽  
Training Set ◽  
Statistical Parameters ◽  
Test Set ◽  
Qsar Models ◽  
Forward Stepwise ◽  
Leave One Out ◽  
External Test

Organic compounds are often exposed to the environment, and have an adverse effect on the environment and human health in the form of mixtures, rather than as single chemicals. In this paper, we try to establish reliable and developed classical quantitative structure–activity relationship (QSAR) models to evaluate the toxicity of 99 binary mixtures. The derived QSAR models were built by forward stepwise multiple linear regression (MLR) and nonlinear radial basis function neural networks (RBFNNs) using the hypothetical descriptors, respectively. The statistical parameters of the MLR model provided were N (number of compounds in training set) = 79, R2 (the correlation coefficient between the predicted and observed activities)= 0.869, LOOq2 (leave-one-out correlation coefficient) = 0.864, F (Fisher’s test) = 165.494, and RMS (root mean square) = 0.599 for the training set, and Next (number of compounds in external test set) = 20, R2 = 0.853, qext2 (leave-one-out correlation coefficient for test set)= 0.825, F = 30.861, and RMS = 0.691 for the external test set. The RBFNN model gave the statistical results, namely N = 79, R2 = 0.925, LOOq2 = 0.924, F = 950.686, RMS = 0.447 for the training set, and Next = 20, R2 = 0.896, qext2 = 0.890, F = 155.424, RMS = 0.547 for the external test set. Both of the MLR and RBFNN models were evaluated by some statistical parameters and methods. The results confirm that the built models are acceptable, and can be used to predict the toxicity of the binary mixtures.

Design, Synthesis and In Vitro Evaluation of 2-Oxo-N-substituted Phenyl- 2H-chromene-3-carboxamide Derivatives as HIV Integrase Strand Transfer Inhibitors

2020 ◽  
Vol 17 (4) ◽  
pp. 418-427
Author(s):  
Pankaj Wadhwa ◽  
Priti Jain ◽  
Hemant R. Jadhav
Keyword(s):  
Diethyl Malonate ◽  
Significant Inhibition ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Design Synthesis ◽  
Molecular Modelling Studies ◽  
Ic50 Values ◽  
Modelling Studies ◽  
Hiv 1

Background: A series of eighteen 2-Oxo-N-substituted phenyl- 2H-chromene-3- carboxamide analogues has been evaluated for HIV-1 integrase (IN) inhibition. Methods: The derivatives were synthesized via a two-step pathway commencing with 2- hydroxybenzaldehyde and diethyl malonate followed by hydrolysis of ester and coupling with various aromatic amines. The HIV-1 IN inhibitory potential of these compounds has been studied relative to dolutegravir, a known HIV-1 IN inhibitor using a standard available kit. Results: Six molecules (compounds 13h, 13i, 13l, 13p to 13r) showed significant inhibition of HIV- 1 integrase 3′-strand transfer with IC50 values less than 1.7 μM. The presence of chromene-3- carboxamide motif was shown to be crucial for the enzymatic activity. In addition, molecular modelling studies were also done to justify the IN inhibition and in vitro-in silico correlation was drawn. Conclusion: However, these compounds did not show HIV-1 and HIV-2 inhibition below their cytotoxic concentration indicating that these compounds cannot be taken further for anti-HIV activity as such and require structural modification.

scholarly journals Synthesis, Biological Activity and Molecular Docking of New Tricyclic Series as α-glucosidase Inhibitors

2018 ◽  
Author(s):  
Hatem A. Abuelizz ◽  
Nor Azman N. I Iwana ◽  
Rohaya Ahmad ◽  
Anouar El-Hassane ◽  
Mohamed Marzouk ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Digestive Enzymes ◽  
Postprandial Glucose ◽  
Glucose Absorption ◽  
Hydrogen Bond Interactions ◽  
Glucosidase Inhibitors ◽  
Molecular Modelling Studies ◽  
Modelling Studies ◽  
Hydrolysis Of ◽  
Postprandial Glucose Level

AbstractDiabetes 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 IC50 of 104.07 mM. Molecular modelling studies revealed that compound 6h inhibits α-glucosidase due to the formation of a stable ligand–α-glucosidase complex and extra hydrogen bond interactions, and directed in the binding site by Trp329.

2,4-Disubstituted Quinazoline Derivatives Act as Inducers of Tubulin Polymerization: Synthesis and Cytotoxicity

2019 ◽  
Vol 19 (8) ◽  
pp. 1048-1057 ◽  
Author(s):  
Ebrahim S. Moghadam ◽  
Maryam H. Tehrani ◽  
René Csuk ◽  
Lucie Fischer ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
Human Tumor ◽  
Cancer Drug ◽  
Tubulin Polymerization ◽  
Highly Active ◽  
Cancer Drug Resistance ◽  
Antimitotic Drugs ◽  
Molecular Modelling Studies ◽  
Ic50 Values ◽  
Modelling Studies ◽  
Quinazoline Derivatives

Background: During last recent years number of anti-tubulin agents were introduced for treatment of diverse kind of cancer. Despite of their potential in treatment of cancer, drug resistance and adverse toxicity such as peripheral neuropathy are some of the negative criteria of anti-tubulin agents. Methods: Twenty seven quinazoline derivatives were synthesized using a multicomponent reaction. The cytotoxicity of compounds 1-27 was tested in SRB assays employing five different human tumor cell lines. Effect of two of active compounds on tubulin polymerization was also checked using a commercially available assay kit. Molecular modelling studies were also performed using autodock tools software. Results: SRB assays showed that compounds 2, 9, 16 and 26, being highly cytotoxic with IC50 values ranging between 2.1 and 14.3µM. The possible mode of action of compounds, 2, 9, 16 and 26, and the taxol binding site of the protein tubulin, an important goal for antimitotic drugs, was also studied by molecular docking, which showed reasonable interactions with tubulin active site, followed by investigation of the effects of compounds 9 and 16 on the polymerization of tubulin. The results showed the tested compounds to be highly active as inducers of tubulin polymerization. Conclusion: Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on quinazoline scaffold as antimitotic agents.

scholarly journals Development of New Multicomponent Reactions in Eco-Friendly Media-Greener Reaction and Expeditious Synthesis of Novel Bioactive Benzylpyranocoumarins

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Hamida Jelali ◽  
A. Chakchouk-Mtibaa ◽  
Lasaad Baklouti ◽  
Hallouma Bilel ◽  
Yaser Bathich ◽  
...  
Keyword(s):  
Density Functional ◽  
Aromatic Aldehydes ◽  
Density Functional Theory Calculations ◽  
Butylated Hydroxytoluene ◽  
Dilution Method ◽  
Coumarin Derivatives ◽  
H Nmr ◽  
Molecular Modelling Studies ◽  
Ic50 Values ◽  
Modelling Studies

Multicomponent cyclocondensation of hydrazine derivatives, ethyl acetoacetate, aromatic aldehydes, and 4-hydroxycoumarin has been reported. The optimization details of the developed novel protocol are recorded. The novel procedure features short reaction time, moderate yields, and simple workup. In addition, BMIM[triflate] was chosen as a green solvent. The structures of the obtained benzylpyrazolyl coumarins were determined and confirmed by 1H NMR, 13C NMR, IR, and elemental analysis. The MIC values of benzylpyrazolyl coumarin derivatives were determined by the microbroth dilution method using 96-well plates. However, the derivatives 5a, 5b, 5d, and 5g possess the strongest activities. Compound 5b was the most active derivative against Candida albicans. Moreover, the antioxidant activity determination of these coumarins derivatives 5(a–g)–6(a–g) were studied with the DPPH and compared with gallic acid (GA)and butylated hydroxytoluene (BHT). Molecular modelling studies using DFT (density functional theory) calculations showed that there two tautomers A and B in which A is more stable than B. The benzylpyrazolyl coumarin derivatives 5e and 6f exhibited the most cytotoxic effect on the promising cytotoxic activity with IC50 values 4.45 μg/mL against MDA-MB-231 and 4.85 μg/mL against MCF7, respectively.

Synthesis of Indolyl Pyrazole Scaffolds as Potential Anti-cancer Agents and their Molecular Modelling Studies

2020 ◽  
Vol 17 (7) ◽  
pp. 828-839
Author(s):  
Ganga Reddy Gaddam ◽  
Pramod Kumar Dubey ◽  
Venkata Ramana Reddy Chittireddy
Keyword(s):  
Cell Lines ◽  
Biological Activities ◽  
Moderate Activity ◽  
Lung Cancer Cell ◽  
Anti Cancer ◽  
A549 Lung Cancer Cell ◽  
New Chemical Entities ◽  
Molecular Modelling Studies ◽  
Modelling Studies ◽  
A549 Lung

Background:: Indole and pyrazoles are one of the prime structural units in the field of medicinal chemistry and have been reported to exhibit a variety of biological activities specifically anti-cancer. In view of their medicinal significance, we synthesized a conjugate of the two moieties to get access to newer and potential anti-cancer agents. Methods: Indolyl pyrazoles [3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(1-methyl-1H-indole-3-carbon yl)acrylonitriles] (4a-l) were synthesized by adopting simple and greener protocol and all the synthesized derivatives were docked against Bcl-2 protein and the selected chemical moieties were screened for their cytotoxicity by using the MTT assay. Results: : All the synthesized compounds were docked against BCL-2 protein in order to understand their binding pattern. Among the 12 compounds docked, 4d, 4f, 4h, 4j, and 4l compounds exhibited better protein binding interactions and the same were screened for their anti-cancer activity against A549 (lung) cancer cell lines at a concentration of 100 μM using Doxorubicin as standard. Substitutions such as N-benzyl, N-ethyl groups and halogen groups such as Br, Cl on indole ring showed moderate activity against A-549 cell lines. Conclusion:: Among the 5 indolyl pyrazole derivatives screened, compounds 4h and 4j showed significantly better activity with an IC50 of 33.12 and 34.24 μM, respectively. Further, structural tweaking of the synthesized new chemical entities may lead to potential hit/lead-like molecules.

Synthesis, Molecular Modeling and Biological Evaluation of 5-arylidene-N,N-diethylthiobarbiturates as Potential α-glucosidase Inhibitors

2019 ◽  
Vol 15 (2) ◽  
pp. 175-185 ◽  
Author(s):  
Momin Khan ◽  
Sehrish Khan ◽  
Amir Ul Mulk ◽  
Anis Ur Rahman ◽  
Abdul Wadood ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Barbituric Acid ◽  
Aromatic Aldehydes ◽  
Biological Evaluation ◽  
Distilled Water ◽  
Sound Effects ◽  
Glucosidase Inhibitors ◽  
Ic50 Values ◽  
Antiviral Activities ◽  
Barbituric Acid Derivatives

Background:Barbituric acid derivatives are a versatile group of compounds which are identified as potential pharmacophores for the treatment of anxiety, epilepsy and other psychiatric disorders. They are also used as anesthetics and have sound effects on the motor and sensory functions. Barbiturates are malonylurea derivatives with a variety of substituents at C-5 position showing resemblance with nitrogen and sulfur containing compounds like thiouracil which exhibited potent anticancer and antiviral activities. Recently, barbituric acid derivatives have also received great interest for applications in nanoscience.Objective:Synthesis of 5-arylidene-N,N-diethylthiobarbiturates, biological evaluation as potential α-glucosidase inhibitors and molecular modeling.Methods:In the present study, N,N-Diethylthiobarbituric acid derivatives were synthesized by refluxing of N,N-diethylthiobarbituric acid and different aromatic aldehydes in distilled water. In a typical reaction; a mixture of N,N-diethylthiobarbituric acid 0.20 g (1 mmol) and 5-bromo-2- hydroxybenzaldehyde 0.199 g (1 mmol) mixed in 10 mL distilled water and reflux for 30 minutes. After completion of the reaction, the corresponding product 1 was filtered and dried and yield calculated. It was crystallized from ethanol. The structures of synthesized compounds 1-25 were carried out by using 1H, 13C NMR, EI spectroscopy and CHN analysis used for the determination of their structures. The α-glucosidase inhibition assay was performed as given by Chapdelaine et al., with slight modifications and optimization.Results:Our newly synthesized compounds showed a varying degree of α-glucosidase inhibition and at least four of them were found as potent inhibitors. Compounds 6, 5, 17, 11 exhibited IC50 values (Mean±SEM) of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 µM, respectively, as compared to standard acarbose (IC50, 38.25 ± 0.12 µM).Conclusion:Our present study has shown that compounds 6, 5, 17, 11 exhibited IC50 values of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 µM, respectively. The studies were supported by in silico data analysis.

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