scholarly journals Synthesis, Molecular Docking Studies and In Silico ADMET Screening of New Heterocycles Linked Thiazole Conjugates as Potent Anti-Hepatic Cancer Agents

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1705
Author(s):  
Huda R. M. Rashdan ◽  
Mohamed El-Naggar ◽  
Aboubakr H. Abdelmonsef
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
Therapeutic Agents ◽  
Hepatic Cancer ◽  
The Novel ◽  
Thiazole Derivatives ◽  
In Silico Admet ◽  
Thiosemicarbazide Derivative ◽  
Cyclocondensation Reaction

Thiazoles are important scaffolds in organic chemistry. Biosynthesis of thiazoles is considered to be an excellent target for the design of novel classes of therapeutic agents. In this study, a new series of 2-ethylidenehydrazono-5-arylazothiazoles 5a–d and 2-ethylidenehydrazono-5-arylazo- thiazolones 8a–d were synthesized via the cyclocondensation reaction of the appropriate hydrazonyl halides 4a–d and 7a–d with ethylidene thiosemicarbazide 3, respectively. Furthermore, the thiosemicarbazide derivative 3 was reacted with different bromoacetyl compounds 10–12 to afford the respective thiazole derivatives 13–15. Chemical composition of the novel derivatives was established on bases of their spectral data (FTIR, 1H-NMR, 13C-NMR and mass spectrometry) and microanalytical data. The newly synthesized derivatives were screened for their in vitro anti-hepatic cancer potency using an MTT assay. Moreover, an in silico technique was used to assess the interaction modes of the compounds with the active site of Rho6 protein. The docking studies of the target Rho6 with the newly synthesized fourteen compounds showed good docking scores with acceptable binding interactions. The presented results revealed that the newly synthesized compounds exhibited promising inhibition activity against hepatic cancer cell lines (HepG2).

scholarly journals Quinazolin-4-one derivatives lacking toxicity-producing attributes as glucokinase activators: design, synthesis, molecular docking, and in-silico ADMET prediction

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Saurabh C. Khadse ◽  
Nikhil D. Amnerkar ◽  
Manasi U. Dave ◽  
Deepak K. Lokwani ◽  
Ravindra R. Patil ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Enzyme Assay ◽  
Binding Free Energy ◽  
Docking Studies ◽  
Oral Glucose ◽  
Substitution Pattern ◽  
Glucokinase Activators ◽  
In Silico Admet

Abstract Background A small library of quinazolin-4-one clubbed thiazole acetates/acetamides lacking toxicity-producing functionalities was designed, synthesized, and evaluated for antidiabetic potential as glucokinase activators (GKA). Molecular docking studies were done in the allosteric site of the human glucokinase (PDB ID: 1V4S) enzyme to assess the binding mode and interactions of synthesized hits for best-fit conformations. All the compounds were evaluated by in vitro enzymatic assay for GK activation. Results Data showed that compounds 3 (EC50 = 632 nM) and 4 (EC50 = 516 nM) showed maximum GK activation compared to the standards RO-281675 and piragliatin. Based on the results of the in vitro enzyme assay, docking studies, and substitution pattern, selected compounds were tested for their glucose-lowering effect in vivo by oral glucose tolerance test (OGTT) in normal rats. Compounds 3 (133 mg/dL) and 4 (135 mg/dL) exhibited prominent activity by lowering the glucose level to almost normal, eliciting the results in parallel to enzyme assay and docking studies. Binding free energy, hydrogen bonding, and π–π interactions of most active quinazolin-4-one derivatives 3 and 4 with key amino acid residues of the 1V4S enzyme were studied precisely. Preliminary in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out using SwissADME and PreADMET online software which revealed that all the compounds have the potential to become orally active antidiabetic agents as they obeyed Lipinski's rule of five. Conclusion The results revealed that the designed lead could be significant for the strategic design of safe, effective, and orally bioavailable quinazolinone derivatives as glucokinase activators.

Synthesis, Antimicrobial Evaluation and In silico Studies of Novel 2,4- disubstituted-1,3-thiazole Derivatives

2018 ◽  
Vol 16 (2) ◽  
pp. 160-173 ◽  
Author(s):  
Mir Mohammad Masood ◽  
Mohammad Irfan ◽  
Shadab Alam ◽  
Phool Hasan ◽  
Aarfa Queen ◽  
...  
Keyword(s):  
In Silico ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Docking Studies ◽  
Bacterial Strains ◽  
Thiazole Derivatives ◽  
Standard Drug ◽  
Hek 293 ◽  
In Silico Studies

Background: 2,4-disubstituted-1,3-thiazole derivatives (2a–j), (3a–f) and (4a–f) were synthesized, characterized and screened for their potential as antimicrobial agents. In the preliminary screening against a panel of bacterial strains, nine compounds showed moderate to potent antibacterial activity (IC50 = 13.7-90.8 μg/ml). </P><P> Methods: In the antifungal screening, compound (4c) displayed potent antifungal activity (IC50 = 26.5 &#181;g/ml) against Candida tropicalis comparable to the standard drug, fluconazole (IC50 = 10.5 &#181;g/ml). Based on in vitro antimicrobial results, compounds 2f, 4c and 4e were selected for further pharmacological investigations. Hemolytic activity using human red blood cells (hRBCs) and cytotoxicity by MTT assay on human embryonic kidney (HEK-293) cells revealed non-toxic nature of the selected compounds (2f, 4c and 4e). To ascertain their possible mode of action, docking studies with the lead inhibitors (2f, 4c and 4e) were performed using crystal structure coordinates of bacterial methionine aminopeptidases (MetAPs), an enzyme involved in bacterial protein synthesis and maturation. Results: The results of in vitro and in silico studies provide a rationale for selected compounds (2f, 4c and 4e) to be carried forward for further structural modifications and structure-activity relationship (SAR) studies against these bacterial infections. Conclusion: The study suggested binding with one or more key amino acid residues in the active site of Streptococcus pneumoniae MetAP (SpMetAP) and Escherichia coli MetAP (EcMetAP). In silico physicochemical properties using QikProp confirmed their drug likeliness.

Synthesis, Biological Evaluation and Molecular Docking Studies of Novel Di-hydropyridine Analogs as Potent Antioxidants

2019 ◽  
Vol 19 (29) ◽  
pp. 2676-2686 ◽  
Author(s):  
Saddala Madhu Sudhana ◽  
Pradeepkiran Jangampalli Adi
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Binding Energies ◽  
Molecular Docking Studies ◽  
Metal Chelating ◽  
In Silico Admet ◽  
Dpph Method

Aims: The aim of this study is to synthesize, characterize and biological evaluation of 3-ethyl 5- methyl2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate derivatives. Background: An efficient synthesis of two series of novel carbamate and sulfonamide derivatives of amlodipine, 3-ethyl 5-methyl 2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (amlodipine) 1 were chemical synthesized process. Materials & Methods: In this process, various chloroformates 2(a-e) and sulfonyl chlorides 4(a-e) on reaction with 1 in the presence of N,N–dimethylpiperazine as a base in THF at 50-550 oC, the corresponding title compounds 3(a-e) and 5(a-e) in high yields. Furthermore, the compounds 3(a-e) and 5(a-e) were evaluated for antioxidant activity (DPPH method), metal chelating activity, hemolytic activity, antioxidant assay (ABTS method), cytotoxicity, molecular docking and in silico ADMET properties. Result: Results revealed that 5a, 5e, 3d, 3a and 5c exhibited high antioxidant, metal chelating activities, but 5a, 5e and 3d exhibited low activity. The molecular docking studies and ADMET of suggested ligands showed the best binding energies and non-toxic properties. Conclusion: The present in silico and in vitro evaluations suggested that these dihydropyridine derivatives act as potent antioxidants and chelating agents which may be useful in treating metals induced oxidative stress associated diseases.

Computational Studies of bis-2-Oxoindoline Succinohydrazides and their In Vitro Cytotoxicity

2020 ◽  
Vol 16 (3) ◽  
pp. 270-280 ◽  
Author(s):  
Ravi Jarapula ◽  
Vishnu N. Badavath ◽  
Shriram Rekulapally ◽  
Sarangapani Manda
Keyword(s):  
Molecular Docking ◽  
Linear Regression ◽  
Cytotoxic Activity ◽  
In Silico ◽  
3D Qsar ◽  
Docking Studies ◽  
Egfr Inhibitors ◽  
Molecular Docking Studies ◽  
In Silico Admet

Background: The discovery of clinically relevant EGFR inhibitors for cancer therapy has proven to be a challenging task. To identify novel and potent EGFR inhibitors, the quantitative structure-activity relationship (QSAR) and molecular docking approach became a very useful and largely widespread technique for drug design. Methods: We performed the in vitro cytotoxic activity on HEPG-2 cell line and earlier on MCF-7 and A 549 by using MTT assay method. The development of 3D QSAR model of N1,N4-bis(2-oxoindolin-3- ylidene) succinohydrazides using the stepwise-backward variable methods to generate Multiple Linear Regression method elucidates the structural properties required for EGFR inhibitory activity and also perform the Molecular Docking studies on EGFR (PDB ID:1M17). Further, we analysed for Lipinski’s rule of five to evaluate the drug-likeness and established in silico ADMET properties. Results: The resulting cytotoxicity (IC50) values ranged from 9.34 to 100 μM and compared with cisplatin as a standard. Among the series of compounds, 6j showed good cytotoxic activity on HEPG-2 cell line with 9.34 μM, IC50 value. Most of the evaluated compounds showed good antitumor activity on HEPG-2 than MCF-7and A549. The developed 3D QSAR Multiple Linear Regression models are statistically significant with non-cross-validated correlation coefficient r2 = 0.9977, cross-validated correlation coefficient q2 = 0.902 and predicted_r2 = 0.9205. Molecular docking studies on EGFR (PDB ID: 1M17) results, compounds 6d, 6j and 6l showed good dock/PLP scores i.e. -81.28, -73.98 and -75.37, respectively, by interacting with Leu-694, Val-702 and Gly-772 amino acids via hydrophobic and hydrogen bonds with Asn818 and Met- 769. Further, we analysed drug-likeness and established in silico ADMET properties. Conclusion: The results of 3D QSAR studies suggest that the electrostatic and steric descriptors influence the cytotoxic activity of succinohydrazides. From the molecular docking studies, it is evident that hydrophobic, hydrogen and Van Der Waal’s interactions determine binding affinities. In addition to this, druglikeness and ADMET properties were analysed. It is evident that there is a correlation between the QSAR and docking results. Compound 6j was found to be too lipophilic due to its dihalo substitution on isatin nucleus, and can act as a lead molecule for further and useful future development of new EGFR Inhibitors.

Synthesis of Novel Aryl (4-Aryl-1h-Pyrrol-3-Yl) (Thiophen-2-Yl) Meth-anone Derivatives: Molecular Modelling, In Silico Admet, Anti-Inflammatory and Anti-Ulcer Activities

2020 ◽  
Vol 19 ◽  
Author(s):  
MD Arif Pasha ◽  
Sumanta Mondal ◽  
Naresh Panigrahi
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
Active Site Residues ◽  
New Class ◽  
In Silico Admet ◽  
Sequential Addition ◽  
Anti Inflammatory ◽  
Cox 1 ◽  
Autodock 4.2

Background:: A series of novel aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives was synthe-sized from sequential addition reaction with chalcones and toluenesulfonylmethyl isocyanide (TosMIC). Methods: The de-rivatives were screened against anti-inflammatory, anti-ulcer activities with an inhibition of 80.65% for PY-5 compound at 200mg/kg and inhibition of 77.5% for PY-1 compound at 200mg/kg. Active anti-inflammatory agents were subjected to in-vitro Cyclooxygenase (COX) inhibition assay. The interactions between the synthesized compounds and active site residues of proteins COX-1 (3N8Y), COX-2 (1PXX), H+/K+ ATPase (2XZB) were investigated by using molecular docking studies using autodock 4.2. Results and Conclusion:: In silico drug likeliness and toxicity prediction studies were carried by OSIRIS property explorer and admetSAR prediction tool which predicts that two compounds of PY-5 and PY-1 shows a new class of potential anti-inflammatory and anti-ulcer agents and serves as new anti-inflammatory and anti-ulcer drugs after further investigation.

In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

2018 ◽  
Vol 21 (3) ◽  
pp. 215-221
Author(s):  
Haroon Khan ◽  
Muhammad Zafar ◽  
Helena Den-Haan ◽  
Horacio Perez-Sanchez ◽  
Mohammad Amjad Kamal
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
In Vivo Studies ◽  
In Vitro Assays ◽  
Chronic Obstructive ◽  
Lipoxygenase Inhibitors ◽  
Lipoxygenase Inhibition ◽  
In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking

2020 ◽  
Vol 23 ◽  
Author(s):  
Sisir Nandi ◽  
Mohit Kumar ◽  
Mridula Saxena ◽  
Anil Kumar Saxena
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Drug Repurposing ◽  
Clinical Settings ◽  
The Novel ◽  
In Silico Docking ◽  
Biochemical Mechanisms ◽  
Novel Coronavirus ◽  
In Silico Molecular Docking

Background: The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective: Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method: In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results: 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion: Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

Acetate Kinase (AcK) is Essential for Microbial Growth and Betel-derived Compounds Potentially Target AcK, PhoP and MDR Proteins in M. tuberculosis, V. cholerae and Pathogenic E. coli: An in silico and in vitro Study

2019 ◽  
Vol 18 (31) ◽  
pp. 2731-2740 ◽  
Author(s):  
Sandeep Tiwari ◽  
Debmalya Barh ◽  
M. Imchen ◽  
Eswar Rao ◽  
Ranjith K. Kumavath ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
In Silico ◽  
Pathogenic Bacteria ◽  
In Vitro Study ◽  
Docking Studies ◽  
Acetate Kinase ◽  
E Coli ◽  
Pathogenic Escherichia Coli ◽  
Novel Target

Background: Mycobacterium tuberculosis, Vibrio cholerae, and pathogenic Escherichia coli are global concerns for public health. The emergence of multi-drug resistant (MDR) strains of these pathogens is creating additional challenges in controlling infections caused by these deadly bacteria. Recently, we reported that Acetate kinase (AcK) could be a broad-spectrum novel target in several bacteria including these pathogens. Methods: Here, using in silico and in vitro approaches we show that (i) AcK is an essential protein in pathogenic bacteria; (ii) natural compounds Chlorogenic acid and Pinoresinol from Piper betel and Piperidine derivative compound 6-oxopiperidine-3-carboxylic acid inhibit the growth of pathogenic E. coli and M. tuberculosis by targeting AcK with equal or higher efficacy than the currently used antibiotics; (iii) molecular modeling and docking studies show interactions between inhibitors and AcK that correlate with the experimental results; (iv) these compounds are highly effective even on MDR strains of these pathogens; (v) further, the compounds may also target bacterial two-component system proteins that help bacteria in expressing the genes related to drug resistance and virulence; and (vi) finally, all the tested compounds are predicted to have drug-like properties. Results and Conclusion: Suggesting that, these Piper betel derived compounds may be further tested for developing a novel class of broad-spectrum drugs against various common and MDR pathogens.

Novel Spiro/non-Spiro Pyranopyrazoles: Eco-Friendly Synthesis, In-vitro Anticancer Activity, DNA Binding, and In-silico Docking Studies

2019 ◽  
Vol 15 (2) ◽  
pp. 257-267 ◽  
Author(s):  
Paritosh Shukla ◽  
Ashok Sharma ◽  
Leena Fageria ◽  
Rajdeep Chowdhury
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
In Silico ◽  
Antimicrobial Agents ◽  
Docking Studies ◽  
Bioactive Molecules ◽  
Microwave Assisted Synthesis ◽  
Binding Affinities ◽  
In Silico Docking

Background: Cancer being a deadly disease, many reports of new chemical entities are available. Pyranopyrazole (PPZ) compounds have also been disclosed as bioactive molecules but mainly as antimicrobial agents. Based on one previous report and our interest in anticancer drug design, we decided to explore PPZs as anticancer agents. To the best of our knowledge, we found that a comprehensive study, involving synthesis, in-vitro biological activity determination, exploration of the mechanism of inhibition and finally in-silico docking studies, was missing in earlier reports. This is what the present study intends to accomplish. Methods: Ten spiro and eleven non-spiro PPZ molecules were synthesized by environment-friendly multicomponent reaction (MCR) strategy. After subjecting each of the newly synthesized molecules to Hep3b hepatocellular carcinoma cell lines assay, we selectively measured the Optical Density (OD) of the most active ones. Then, the compound exhibiting the best activity was docked against human CHK- 1 protein to get an insight into the binding affinities and a quick structure activity relationship (SAR) of the PPZs. Results: The two series of spiro and non-spiro PPZs were easily synthesized in high yields using microwave assisted synthesis and other methods. Among the synthesized compounds, most compounds showed moderate to good anticancer activity against the MTT assay. After performing the absorbance studies we found that the non-spiro molecules showed better apoptosis results and appeared to bind to DNA causing disruption in their structures. Finally, the docking results of compound 5h (having N,Ndimethylamino substituted moiety) clearly showed good binding affinities as predicted by our experimental findings. Conclusion: The paper describes a comprehensive synthesis, in-vitro and docking studies done on new PPZs. The newly synthesized series of spiro and non-spiro PPZs were found to possess antineoplasmic activity as evinced by the studies on hep3b cells. Also, the UV visible absorbance study gave clues to the possible binding of these molecules to the DNA. Docking studies corroborated well with the experimental results. Thus, these new molecules appear to be potential anticancer agents, but further studies are required to substantiate and elaborate on these findings.

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