Synthesis, structures, drug-likeness, in vitro evaluation and in silico docking on novel N-benzoyl-N′-phenyl thiourea derivatives

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.

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Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents

Current Alzheimer Research ◽

10.2174/1567205016666181212155147 ◽

2019 ◽

Vol 16 (2) ◽

pp. 116-127 ◽

Cited By ~ 2

Author(s):

Ashwani Kumar ◽

Vineet Mehta ◽

Utkarsh Raj ◽

Pritish Kumar Varadwaj ◽

Malairaman Udayabanu ◽

...

Keyword(s):

In Silico ◽

Hippocampal Neurons ◽

Symptomatic Relief ◽

In Vitro Assays ◽

Disease Modifying Drugs ◽

In Silico Docking ◽

Ache Inhibitors ◽

Significant Difference ◽

Disease Modifying

Background: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer’s disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer ‘disease-modifying drugs’. Methods: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. Results: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do. Conclusion: Quercetin and caffeine have the potential as “disease-modifying drugs” and may find application in the management of neurological disorders such as AD.

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α-Glucosidase Inhibition, Antioxidant and Docking Studies of Hydroxycoumarins and their Mono and Bis O-alkylated/acetylated Analogs

Letters in Drug Design & Discovery ◽

10.2174/1570180814666170602081941 ◽

2018 ◽

Vol 15 (2) ◽

pp. 127-135 ◽

Cited By ~ 3

Author(s):

Parvesh Singh ◽

Nomandla Ngcoya ◽

Ramgopal Mopuri ◽

Nagaraju Kerru ◽

Neha Manhas ◽

...

Keyword(s):

In Silico ◽

Biological Activities ◽

Wide Spectrum ◽

Radical Scavenging Activity ◽

Radical Scavenging ◽

Catalytic Site ◽

Docking Simulations ◽

In Silico Docking ◽

Anti Oxidant

Background: Diabetes Mellitus (DM) is a complex metabolic disease illustrated by abnormally high levels of plasma glucose or hyperglycaemia. Accordingly, several α-glucosidase inhibitors have been developed for the treatment of diabetes and other degenerative disorders. While, a coumarin ring has the privilege to represent numerous natural and synthetic compounds with a wide spectrum of biological activities e.g. anti-cancer, anti-HIV, anti-viral, anti-malarial, anti-microbial, anti-convulsant, anti-hypertensive properties. Besides this, coumarins have also shown potential to inhibit α-glucosidase leading to a generation of new promising antidiabetic agents. However, the testing of O-substituted coumarins for α-glucosidase inhibition has evaded the attention of medicinal chemists. Methods: For O-alkylation/acetylation reactions, the hydroxyl coumarins (A-B) initially activated by K2CO3 in dry DMF were reacted with variedly substituted haloalkanes at room temperature under nitrogen. The synthesized compounds were tested for their α-glucosidase (from Saccharomyces cerevisiae) inhibitory activity and anti-oxidant activity using DPPH radical scavenging activity. In silico docking simulations were conducted using CDocker module in DS (Accelrys) to explore the binding modes of the representative compounds in the catalytic site of α-glucosidase. Results: All the coumarin analogues (A1, B1, A2-A10, B2-B8) including their precursors (A-B) were evaluated for their in vitro α-glucosidase inhibition using acarbose as a standard inhibitor. All the mono O-alkylated coumarins (except A1) showed significant (p <0.05) α-glucosidase inhibition relative to the hydroxyl coumarin (A) with IC50 values ranging between 11.084±0.117 to 145.24± 29.22 µg/mL. Compound 7-(benzyloxy)-4, 5-dimethyl-2H-chromen-2-one (A9) bearing a benzyl group (Ph-CH2-) at position 7 showed a remarkable (p <0.05) increase in the activity (IC50 = 11.084±0.117 µg/mL), almost four-fold more than acarbose (IC50 = 40.578±5.999 µg/mL). The introduction of –NO2 group dramatically improved the anti-oxidant activity of coumarin, while the O-alkylation/acetylation decreased the activity. Conclusion: The present study describes the synthesis of functionalized coumarins and their evaluation for α-glucosidase inhibition and antioxidant activity under in vitro conditions. Based on IC50 data, the mono O-alkylated coumarins were observed to be stronger inhibitors of α-glucosidase with respect to their bis O-alkylated analogues. Coumarin (A9) bearing O-benzyloxy group displayed the strongest α-glucosidase inhibition, even higher than the standard inhibitor acarbose. The coumarin (A10) bearing –NO2 group showed the highest anti-oxidant activity amongst the synthesized compounds, almost comparable to the ascorbic acid. Finally, in silico docking simulations revealed the role of hydrogen bonding and hydrophobic forces in locking the compounds in catalytic site of α-glucosidase.

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Design, Synthesis, In vitro and In silico Evaluation of New Hydrazonebased Antitumor Agents as Potent Akt Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200618163507 ◽

2020 ◽

Vol 17 (11) ◽

pp. 1380-1392

Author(s):

Emine Merve Güngör ◽

Mehlika Dilek Altıntop ◽

Belgin Sever ◽

Gülşen Akalın Çiftçi

Keyword(s):

Cell Line ◽

Anticancer Agents ◽

In Silico ◽

Antitumor Agents ◽

Colorimetric Assay ◽

Fibroblast Cell ◽

Lipinski’S Rule ◽

In Silico Docking ◽

Embryonic Fibroblast

Background: Akt is overexpressed or activated in a variety of human cancers, including gliomas, lung, breast, ovarian, gastric and pancreatic carcinomas. Akt inhibition leads to the induction of apoptosis and inhibition of tumor growth and therefore extensive efforts have been devoted to the discovery of potent antitumor drugs targeting Akt. Objectives: The objective of this work was to identify potent anticancer agents targeting Akt. Methods: New hydrazone derivatives were synthesized and investigated for their cytotoxic effects on 5RP7 H-ras oncogene transformed rat embryonic fibroblast and L929 mouse embryonic fibroblast cell lines. Besides, the apoptotic effects of the most active compounds on 5RP7 cell line were evaluated using flow cytometry. Their Akt inhibitory effects were also investigated using a colorimetric assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package. Results and Discussion: Compounds 3a, 3d, 3g and 3j were found to be effective on 5RP7 cells (with IC50 values of <0.97, <0.97, 1.13±0.06 and <0.97 μg/mL, respectively) when compared with cisplatin (IC50= 1.87±0.15 μg/mL). It was determined that these four compounds significantly induced apoptosis in 5RP7 cell line. Among them, N'-benzylidene-2-[(4-(4-methoxyphenyl)pyrimidin- 2-yl)thio]acetohydrazide (3g) significantly inhibited Akt (IC50= 0.5±0.08 μg/mL) when compared with GSK690693 (IC50= 0.6±0.05 μg/mL). Docking studies suggested that compound 3g showed good affinity to the active site of Akt (PDB code: 2JDO). According to in silico ADME studies, the compound also complies with Lipinski's rule of five and Jorgensen's rule of three. Conclusion: Compound 3g stands out as a potential orally bioavailable cytotoxic agent and apoptosis inducer targeting Akt.

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

Current Bioactive Compounds ◽

10.2174/1573407213666170828165512 ◽

2019 ◽

Vol 15 (2) ◽

pp. 257-267 ◽

Cited By ~ 3

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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Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.1080/14756366.2021.1916009 ◽

2021 ◽

Vol 36 (1) ◽

pp. 1370-1377

Author(s):

Daniel A. S. Kitagawa ◽

Rafael B. Rodrigues ◽

Thiago N. Silva ◽

Wellington V. dos Santos ◽

Vinicius C. V. da Rocha ◽

...

Keyword(s):

In Silico ◽

Design Synthesis ◽

In Vitro Evaluation ◽

In Silico Studies ◽

Acetylcholinesterase Reactivators

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In Silico Docking and In Vitro Approaches towards BACE1 and Cholinesterases Inhibitory Effect of Citrus Flavanones

Molecules ◽

10.3390/molecules23071509 ◽

2018 ◽

Vol 23 (7) ◽

pp. 1509 ◽

Cited By ~ 11

Author(s):

Seungeun Lee ◽

Kumju Youn ◽

GyuTae Lim ◽

Jinhyuk Lee ◽

Mira Jun

Keyword(s):

In Silico ◽

Inhibitory Effect ◽

In Silico Docking

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Oleuropein modulates over-proliferation of keratinocytes in mice with imiquimodmediated psoriasis and inhibits differentiation of TH17 cells through the JAK3/STAT3 axis

Archives of Medical Science ◽

10.5114/aoms.2020.100642 ◽

2020 ◽

Author(s):

Quan Shi ◽

Qi He ◽

Weiming Chen ◽

Jianwen Long ◽

Bo Zhang

Keyword(s):

T Cells ◽

In Silico ◽

Th17 Cells ◽

Skin Lesions ◽

Docking Studies ◽

Inflammatory Disorder ◽

T Helper 17 ◽

In Silico Docking

IntroductionOleuropein (OLP) is polyphenol obtained from olive oil; it is proved in Chinese traditional medicine for its use in disorders including autoimmune and inflammatory disorders. Psoriasis (PSR) is an autoimmune and inflammatory disorder triggered by T-helper-17 (Th17) cells.Material and methodsWe developed an imiquimod (IMQ)-mediated PSR model in mice to study the anti-inflammatory role of OLP in psoriasis. The mice were given 50 mg/kg and 100 mg/kg dose of OLP. Histology was done to assess the inflammation of lesions. Western blot analysis was done for JAK3/STAT3 in isolated T cells, expression of RORgt was done by RT-PCR. The In silico molecular docking studies were done for interaction of OLP with target protein STAT3 and JAK3.ResultsTreatment of OLP attenuated proliferation in IMQ-mediated keratinocytes, improved infiltration of CD3+ cells in the skin lesions and in CD4+ and CD8+ T cells and also ameliorated the levels of cytokines. In in vitro studies in isolated T cells, OLP blocked the differentiation of Th17 cells and also the levels of IL-17 and the JAK3/STAT3 pathway. The in silico docking showed that OLP had potential binding affinity with JAK3 and STAT3 which was parallel to in vivo and in vitro findings.ConclusionsOLP ameliorates psoriasis skin lesions by blocking Th17-mediated inflammation. OLP may be an interesting molecule for treating autoimmunity in psoriasis.

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