Ionic liquid catalysed multicomponent synthesis, antifungal activity, docking studies and in silico ADMET properties of novel fused Chromeno-Pyrazolo-Phthalazine derivatives

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.

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Antimicrobial Activity of Nitrogen-Containing 5-α-Androstane Derivatives: In Silico and Experimental Studies

Antibiotics ◽

10.3390/antibiotics9050224 ◽

2020 ◽

Vol 9 (5) ◽

pp. 224 ◽

Cited By ~ 1

Author(s):

Lela Amiranashvili ◽

Nanuli Nadaraia ◽

Maia Merlani ◽

Charalampos Kamoutsis ◽

Anthi Petrou ◽

...

Keyword(s):

Antimicrobial Activity ◽

Antifungal Activity ◽

In Silico ◽

Web Applications ◽

Experimental Studies ◽

Docking Studies ◽

Minimum Fungicidal Concentration ◽

Antibacterial And Antifungal ◽

Mic Minimum Inhibitory Concentration ◽

Androstane Derivatives

We evaluated the antimicrobial activity of thirty-one nitrogen-containing 5-α-androstane derivatives in silico using computer program PASS (Prediction of Activity Spectra for Substances) and freely available PASS-based web applications (such as Way2Drug). Antibacterial activity was predicted for 27 out of 31 molecules; antifungal activity was predicted for 25 out of 31 compounds. The results of experiments, which we conducted to study the antimicrobial activity, are in agreement with the predictions. All compounds were found to be active with MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration) values in the range of 0.0005–0.6 mg/mL. The activity of all studied 5-α-androstane derivatives exceeded or was equal to those of Streptomycin and, except for the 3β-hydroxy-17α-aza-d-homo-5α-androstane-17-one, all molecules were more active than Ampicillin. Activity against the resistant strains of E. coli, P. aeruginosa, and methicillin-resistant Staphylococcus aureus was also shown in experiments. Antifungal activity was determined with MIC and MFC (Minimum Fungicidal Concentration) values varying from 0.007 to 0.6 mg/mL. Most of the compounds were found to be more potent than the reference drugs Bifonazole and Ketoconazole. According to the results of docking studies, the putative targets for antibacterial and antifungal activity are UDP-N-acetylenolpyruvoylglucosamine reductase and 14-α-demethylase, respectively. In silico assessments of the acute rodent toxicity and cytotoxicity obtained using GUSAR (General Unrestricted Structure-Activity Relationships) and CLC-Pred (Cell Line Cytotoxicity Predictor) web-services were low for the majority of compounds under study, which contributes to the chances for those compounds to advance in the development.

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Natural based piperine derivatives as potent monoamine oxidase inhibitors: an in silico ADMET analysis and molecular docking studies

BMC Chemistry ◽

10.1186/s13065-020-0661-0 ◽

2020 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

Priyanka Dhiman ◽

Neelam Malik ◽

Anurag Khatkar

Keyword(s):

Molecular Docking ◽

Monoamine Oxidase ◽

In Silico ◽

Docking Studies ◽

Monoamine Oxidase Inhibitors ◽

Molecular Docking Studies ◽

In Silico Admet

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Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[d]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium falciparum Adenylosuccinate Lyase Receptor

Bioinformatics and Biology Insights ◽

10.1177/1177932219865533 ◽

2019 ◽

Vol 13 ◽

pp. 117793221986553 ◽

Cited By ~ 1

Author(s):

Gbolahan O Oduselu ◽

Olayinka O Ajani ◽

Yvonne U Ajamma ◽

Benedikt Brors ◽

Ezekiel Adebiyi

Keyword(s):

Plasmodium Falciparum ◽

Molecular Docking ◽

In Silico ◽

Homology Modelling ◽

3D Structure ◽

Docking Studies ◽

Binding Energies ◽

Benzimidazole Derivatives ◽

Adenylosuccinate Lyase ◽

In Silico Admet

Plasmodium falciparum adenylosuccinate lyase ( PfADSL) is an important enzyme in purine metabolism. Although several benzimidazole derivatives have been commercially developed into drugs, the template design as inhibitor against PfADSL has not been fully explored. This study aims to model the 3-dimensional (3D) structure of PfADSL, design and predict in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) of 8 substituted benzo[ d]imidazol-1-yl)methyl)benzimidamide compounds as well as predict the potential interaction modes and binding affinities of the designed ligands with the modelled PfADSL. PfADSL 3D structure was modelled using SWISS-MODEL, whereas the compounds were designed using ChemDraw Professional. ADMET predictions were done using OSIRIS Property Explorer and Swiss ADME, whereas molecular docking was done with AutoDock Tools. All designed compounds exhibited good in silico ADMET properties, hence can be considered safe for drug development. Binding energies ranged from −6.85 to −8.75 kcal/mol. Thus, they could be further synthesised and developed into active commercial antimalarial drugs.

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Molecular docking studies, in-silico ADMET screening, MM-GBSA binding free energy of some novel chalcone substituted 9-anilinoacridines as topoisomerase II inhibitors

International Journal of Computational Biology and Drug Design ◽

10.1504/ijcbdd.2020.10033058 ◽

2020 ◽

Vol 13 (4) ◽

pp. 347

Author(s):

G. Rathika ◽

A. Pandiselvi ◽

Rajagopal Kalirajan ◽

K. Iniyavan

Keyword(s):

Free Energy ◽

Molecular Docking ◽

In Silico ◽

Topoisomerase Ii ◽

Binding Free Energy ◽

Docking Studies ◽

Molecular Docking Studies ◽

Topoisomerase Ii Inhibitors ◽

In Silico Admet

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Synthesis, docking studies, and in silico ADMET predictions of some new derivatives of pyrimidine as potential KSP inhibitors

Medicinal Chemistry Research ◽

10.1007/s00044-014-1120-z ◽

2014 ◽

Vol 24 (1) ◽

pp. 304-315 ◽

Cited By ~ 6

Author(s):

Umer Rashid ◽

Syed Fahad Hassan ◽

Samina Nazir ◽

Abdul Wadood ◽

Muhammad Waseem ◽

...

Keyword(s):

In Silico ◽

Docking Studies ◽

In Silico Admet ◽

Ksp Inhibitors ◽

Derivatives Of

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Activity of Thiazine substituted 9-anilinoacridines against Corona virus (COVID19): An In-silico approach

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11ispl1.2835 ◽

2020 ◽

Vol 11 (SPL1) ◽

pp. 482-490

Author(s):

Kalirajan Rajagopal ◽

Potlapati Varakumar ◽

Baliwada Aparna ◽

Vulsi Bodhya Sri ◽

Gowramma Byran ◽

...

Keyword(s):

In Silico ◽

Binding Free Energy ◽

Viral Disease ◽

Docking Studies ◽

Binding Modes ◽

Main Protease ◽

In Silico Admet ◽

In Silico Studies ◽

Life Threatening ◽

Similar Mode

Coronavirus Disease 2019 (COVID-19), a life-threatening viral disease affected first in Wuhan, China, and quickly spread to more than 200 countries in the world in the year 2020. So many scientists are trying to discover novel drugs and vaccines for coronavirus and treatment for COVID-19. In the present article, in-silico studies have been performed to explore the binding modes of Thiazine substituted 9-anilinoacridines (1a-z) against SARS CoV 2 main protease (PDB id - 5R82) targeting the coronavirus using Schrodinger suit 2019-4. The molecular docking studies are performed by Glide module, in-silico ADMET screening was performed by Qik prop module, and the binding free energy of ligands was calculated using PRIME MM-GB/SA module of Schrodinger suite 2019-4, Maestro 21.2 version. From the in-silico results, Thiazine substituted 9-anilinoacridines like 1m, 1j, 1s and 1b are significantly active against SARS CoV 2 main protease with Glide score more than -5.4 when compared with the currently recommended drug for COVID19, Hydroxychloroquine (G score -5.47). The docking results of the Thiazine substituted 9-anilinoacridines exhibited similar mode of interactions with COVID19 and the residues GLN19, THR24, THR25, THR26, LEU27, HIE41, SER46, MET49, ASN142, GLN143, HIE164, MET165, ASP187, ARG188 and GLN189, play a crucial role in binding with ligands.

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In Silico ADMET and Docking Studies of Thiazolidinedione-acetic-acid Hybrids as Antidiabetics with Cardioprotection

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200618103328 ◽

2020 ◽

Vol 17 (12) ◽

pp. 1475-1484

Author(s):

Deepanwita Maji ◽

Subir Samanta ◽

Vaishali M. Patil

Keyword(s):

Acetic Acid ◽

Amino Acid ◽

Side Effects ◽

In Silico ◽

Methyl Esters ◽

Antioxidant Properties ◽

Docking Studies ◽

Single Amino Acid ◽

In Silico Admet ◽

In Silico Studies

Background: Type-2-diabetes mellitus is associated with many side effects affecting vital body organs, especially heart. Thiazolidinediones are potent antidiabetics. Studies have proven that amino-acids and peptides promote glucose transport, have antioxidant properties, and fewer side effects, thus we designed hybrids by combining amino-acid esters and peptide esters with 2, 4 thiazolidinedione acetic acid moiety which can act as antidiabetic agent with cardioprotection properties. Methodology: In vitro ADME, toxicity, and docking studies were performed using Qikprop3.1.OSIRIS, PROTOX (Prediction of Rodent Oral Toxicity), and FlexX 2.1.3, respectively. Results: All the designed molecules belong to three sub-series, i.e. 2, 4-dioxothiazolidine-5-acetic acid single amino acid hybrid methyl esters, 2, 4-dioxothiazolidine-5-acetic acid dipeptide hybrid methyl esters and 2, 4-dioxothiazolidine-5-acetic acid tripeptide hybrid methyl esters. All molecules were non-toxic. SSMA2, SSMA14, SSMA49, and SSDM50 showed good docking scores in 2PRG and 2UV4, respectively. Conclusion: The selected in silico studies helped to design hybrids with less toxicity, target specificity with dual activity as potential anti-diabetic and cardioprotective agents.

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