1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors.

2020 ◽  
Vol 21 ◽  
Author(s):  
Elizabeth Eldhose ◽  
Kaviarasan Lakshmanan ◽  
Praveen T. Krishnamurthy ◽  
Kalirajan Rajagopal ◽  
Manal Mohammed ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
In Silico ◽  
Biological Activities ◽  
Docking Study ◽  
Binding Mode ◽  
Oral Toxicity ◽  
Standard Drug ◽  
In Silico Docking

Background: 1,3,4-thiadiazolo pyrimidine is a lead molécule which is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity. Objective: The objective of the study was to synthesize series of 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] - [1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivative and evaluated for their possible in vitro and in vivo anticancer activity. Methods: Herein we report the synthetic scheme which was followed for the preparation of a series of title compounds B1- B9 is outlined in the scheme 1. The intermediate 5-[(naphthalen-2- yloxy)methyl]-1,3,4-thiadiazolo-2-amine was prepared by heating 2-naphthoxyacetic acid and thiosemicarbazide in presence of phosphoryl chloride at a temperature of 65 - 750C. The obtained compound reacted with malononitrile and appropriate amount of aromatic and heteroaromatic aldehydes in refluxing ethanol yielded 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives (B1 – B9). The purity of synthesized compounds ensured by various spectral analysis. Results: In in-silico molecular docking studies compounds B3 and B9 show binding affinity like known PARP1 inhibitor olaparib. The cellular evaluation indicates that the anticancer activity of compounds B1, B3, B9 is significant when compared to standard drug (olaparib) against MDA-MB-232 cell line and compounds B3, B6, B7 are most active against MCF-7 cell lines. The most active compound B3 was subjected to acute oral toxicity studies by OECD 423 guidelines and in-vivo anti-cancer studies were carried out using DMBA induced model. Conclusion: The in-silico docking study of the newly synthesized compounds were performed, the results showed good binding mode in the active site of PARP1 enzyme. In-silico ADME properties of synthesized compounds were also studied and showed good drug like properties.

2,4-Dioxochroman Moiety Linked to 1,2,3-triazole Derivatives as Novel α-glucosidase Inhibitors: Synthesis, In vitro Biological Evaluation, and Docking Study

2020 ◽  
Vol 24 (17) ◽  
pp. 2019-2027 ◽  
Author(s):  
Marjan Mollazadeh ◽  
Maryam Mohammadi-Khanaposhtani ◽  
Yousef Valizadeh ◽  
Afsaneh Zonouzi ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
In Silico ◽  
Click Reaction ◽  
Docking Study ◽  
Competitive Inhibitor ◽  
Biological Evaluation ◽  
Binding Energies ◽  
Standard Drug ◽  
In Silico Docking ◽  
Glucosidase Inhibitors

In this study, a novel series of 2,4-dioxochroman-1,2,3-triazole hybrids 8a-l was synthesized by click reaction. These compounds were screened against α-glucosidase through in vitro and in silico evaluations. All the synthesized hybrids exhibited excellent α-glucosidase inhibition in comparison to standard drug acarbose. Representatively, 3-((((1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)methylene)chroman-2,4- dione 8h with IC50 = 20.1 ± 1.5 μM against α-glucosidase, was 37-times more potent than acarbose. Enzyme kinetic study revealed that compound 8h was a competitive inhibitor against α-glucosidase. In silico docking study on chloro derivatives 8h, 8g, and 8i were also performed in the active site of α -glucosidase. Evaluations on obtained interaction modes and binding energies of these compounds confirmed the results obtained through in vitro α-glucosidase inhibition.

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

2018 ◽  
Vol 15 (2) ◽  
pp. 127-135 ◽  
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.

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.

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

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.

scholarly journals SYNTHESIS AND CHARACTERIZATION OF CYCLOHEXANE-1,3-DIONE DERIVATIVES AND THEIR IN SILICO AND IN VITRO STUDIES ON ANTIMICROBIAL AND BREAST CANCER ACTIVITY

2019 ◽  
pp. 311-320 ◽  
Author(s):  
RAJA CHINNAMANAYAKAR ◽  
EZHILARASI MR ◽  
PRABHA B ◽  
KULANDHAIVEL M
Keyword(s):  
Breast Cancer ◽  
Antimicrobial Activity ◽  
Anticancer Activity ◽  
Mtt Assay ◽  
In Silico ◽  
Biologically Active ◽  
Diffusion Method ◽  
Breast Adenocarcinoma ◽  
In Silico Docking

Objective: The objective of this study was to evaluate in silico and in vitro anticancer activity for synthesized cyclohexane-1,3-dione derivatives. Methods: The new series of cyclohexane-1,3-dione derivatives were synthesized based on the Michael addition reaction. Further, the structures of the synthesized compounds were confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), and 13C NMR spectral data. Then, the in silico molecular docking studies were carried out using AutoDock tool version 1.5.6 and AutoDock version 4.2.5.1 docking program. The antimicrobial activity was carried out using the agar disk diffusion method, and the in vitro anticancer activity was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for the synthesized compound. Results: In silico docking study, compound 5c showed good binding score and binding interactions with selected bacterial proteins and breast cancer protein. Further, compound (5a-5h) was tested for their antimicrobial activity and compound 5c was only tested for anticancer activity (human breast adenocarcinoma 3,4-methylenedioxyamphetamine-MB-231 cell line). Compound 5c was found to be the most active one of all the tested compounds. In the MTT assay compound, 5c showed the LC50 value of 10.31±0.003 μg/ml. In antimicrobial activity, the minimum inhibitory concentration of compound 5c is 2.5 mg/ml. Conclusion: An efficient synthesis of biologically active cyclohexane-1, 3-dione derivatives has been developed.

Chemical synthesis and characterization of a new quinazolinedione competitive antagonist for strigolactone receptors with an unexpected binding mode

2019 ◽  
Vol 476 (12) ◽  
pp. 1843-1856 ◽  
Author(s):  
Cyril Hamiaux ◽  
Lesley Larsen ◽  
Hui Wen Lee ◽  
Zhiwei Luo ◽  
Prachi Sharma ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Mode ◽  
Crystal Structure Analysis ◽  
Tolfenamic Acid ◽  
In Vitro Assays ◽  
Inhibition Mechanism ◽  
In Planta ◽  
Competitive Antagonist ◽  
In Silico Docking

Abstract Strigolactones (SLs) are multifunctional plant hormones regulating essential physiological processes affecting growth and development. In vascular plants, SLs are recognized by α/β hydrolase-fold proteins from the D14/DAD2 (Dwarf14/Decreased Apical Dominance 2) family in the initial step of the signaling pathway. We have previously discovered that N-phenylanthranilic acid derivatives (e.g. tolfenamic acid) are potent antagonists of SL receptors, prompting us to design quinazolinone and quinazolinedione derivatives (QADs and QADDs, respectively) as second-generation antagonists. Initial in silico docking studies suggested that these compounds would bind to DAD2, the petunia SL receptor, with higher affinity than the first-generation compounds. However, only one of the QADs/QADDs tested in in vitro assays acted as a competitive antagonist of SL receptors, with reduced affinity and potency compared with its N-phenylanthranilic acid ‘parent’. X-ray crystal structure analysis revealed that the binding mode of the active QADD inside DAD2's cavity was not that predicted in silico, highlighting a novel inhibition mechanism for SL receptors. Despite a ∼10-fold difference in potency in vitro, the QADD and tolfenamic acid had comparable activity in planta, suggesting that the QADD compensates for lower potency with increased bioavailability. Altogether, our results establish this QADD as a novel lead compound towards the development of potent and bioavailable antagonists of SL receptors.

Antiviral Potential of Spondias mombin L. Leaves Extract Against Herpes Simplex Virus Type-1 Replication Using In Vitro and In Silico Approaches

Planta Medica ◽  
2020 ◽  
Vol 86 (07) ◽  
pp. 505-515 ◽  
Author(s):  
Emerson M. da S. Siqueira ◽  
Tábata L. C. Lima ◽  
Laurita Boff ◽  
Sarah G. M. Lima ◽  
Estela M. G. Lourenço ◽  
...  
Keyword(s):  
In Silico ◽  
Therapeutic Potential ◽  
Binding Mode ◽  
Surface Glycoprotein ◽  
Viral Attachment ◽  
Docking Simulations ◽  
Simplex Virus ◽  
Hsv 1

Abstract Spondias mobin leaves have been traditionally used for treating cold sores. The study investigated the mechanism of antiherpes action of S. mombin extract, fractions, and geraniin. Different concentrations of samples were used to evaluate the in vitro antiherpes activity (anti-HSV-1) in virucidal, post-infection, attachment, and penetration assays. The mechanism of action of geraniin was investigated considering the glycoproteins gB and gD of HSV-1 surface as potential molecular targets. Molecular docking simulations were carried out for both in order to determine the possible binding mode position of geraniin at the activity sites. The binding mode position was posteriorly optimized considering the flexibility of the glycoproteins. The chemical analysis of samples was performed by LC-MS and revealed the presence of 22 substances, which are hydrolysable tannins, O-glycosylated flavonoids, phenolic acids, and a carbohydrate. The extract, tannin-rich fraction and geraniin showed important in vitro virucidal activity through blocking viral attachment but showed no relevant inhibition of viral penetration. The in silico approaches demonstrated a high number of potential strong intermolecular interactions as hydrogen bonds between geraniin and the activity site of the glycoproteins, particularly the glycoprotein gB. In silico experiments indicated that geraniin is at least partially responsible for the anti-herpes activity through interaction with the viral surface glycoprotein gB, which is responsible for viral adsorption. These results highlight the therapeutic potential of S. mombin anti-herpes treatment and provides support for its traditional purposes. However, further studies are required to validate the antiviral activities in vivo, as well as efficacy in humans.

scholarly journals In-silico Molecular Docking and ADME/Pharmacokinetic Prediction Studies of Some Novel Carboxamide Derivatives as Anti-tubercular Agents

2020 ◽  
Vol 3 (4) ◽  
pp. 989-1000
Author(s):  
Mustapha Abdullahi ◽  
Shola Elijah Adeniji
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
In Silico ◽  
Density Functional ◽  
Docking Simulation ◽  
Basis Set ◽  
Hybrid Functional ◽  
Standard Drug

AbstractMolecular docking simulation of thirty-five (35) molecules of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamide (IPA) with Mycobacterium tuberculosis target (DNA gyrase) was carried out so as to evaluate their theoretical binding affinities. The chemical structure of the molecules was accurately drawn using ChemDraw Ultra software, then optimized at density functional theory (DFT) using Becke’s three-parameter Lee–Yang–Parr hybrid functional (B3LYP/6-311**) basis set in a vacuum of Spartan 14 software. Subsequently, the docking operation was carried out using PyRx virtual screening software. Molecule 35 (M35) with the highest binding affinity of − 7.2 kcal/mol was selected as the lead molecule for structural modification which led to the development of four (4) newly hypothetical molecules D1, D2, D3 and D4. In addition, the D4 molecule with the highest binding affinity value of − 9.4 kcal/mol formed more H-bond interactions signifying better orientation of the ligand in the binding site compared to M35 and isoniazid standard drug. In-silico ADME and drug-likeness prediction of the molecules showed good pharmacokinetic properties having high gastrointestinal absorption, orally bioavailable, and less toxic. The outcome of the present research strengthens the relevance of these compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis which could help the medicinal chemists and pharmaceutical professionals in further designing and synthesis of more potent drug candidates. Moreover, the research also encouraged the in vivo and in vitro evaluation study for the proposed designed compounds to validate the computational findings.

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