scholarly journals Synthesis, Anticonvulsant Evaluation and Molecular Docking Studies of Novel Benzo[1,3]dioxol-5-yloxy-N′-(4-substituted benzylidene)acetohydrazide Derivatives

2019 ◽  
Vol 32 (1) ◽  
pp. 199-204
Author(s):  
Shailesh Kumar Singh ◽  
Laxmi Tripathi
Keyword(s):  
Molecular Docking ◽  
Mechanism Of Action ◽  
Anticonvulsant Activity ◽  
Docking Studies ◽  
Probable Mechanism ◽  
Aminobutyric Acid ◽  
Docking Score ◽  
Acid Receptor ◽  
Seizure Models ◽  
Gabaergic Activity

Novel (benzo[1,3]dioxol-5-yloxy)-N′-(4-substituted benzylidene)acetohydrazide derivatives were synthesized and their anticonvulsant activity evaluated by MES and scMET seizure models. Compound 2-(benzo[d][1,3]dioxol-5-yloxy)-N′-benzylideneacetohydrazide (4a) was found to be most potent in MES seizure test and showed no neurotoxicity at the highest administered dose. All the compounds showed high docking score with γ-aminobutyric acid receptor, GABAAR-β3 homopentamer (PDB ID: 4COF). Thus, the probable mechanism of action of benzo[1,3]dioxol-5-yloxy-N′-(4-substituted benzylidene)acetohydrazide derivatives (4a-h) may be augmentation of GABAergic activity.

Microwave Assisted Synthesis And Molecular Docking Studies Of Some 4 - (3h)-Quinazolinone Derivatives As Inhibitors Of Human Gamma-Aminobutyric Acid Receptor, The Gaba (A)R-Beta3 Homopentamer

2019 ◽  
Vol 16 ◽  
Author(s):  
Amrutkar Rakesh Devidas ◽  
Mahendra Sing Ranawat
Keyword(s):  
Molecular Docking ◽  
Anthranilic Acid ◽  
Docking Studies ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Ligand Interaction ◽  
Gaba A ◽  
Acid Receptor ◽  
Molecular Docking Studies ◽  
Anti Inflammatory

Background: Quinazolines and quinazolinones constitute a major class of biologically active molecules both from natural and synthetic sources. The quinazolinone moiety is an important pharmacophore showing many types of pharmacological activities as shown in recent exhaustive review on the chemistry of 2-heteroaryl & heteroalkyl-4-quinazolinones4-quinazolinones are the formal condensation products of anthranilic acid and amides, and they can also be prepared in this fashion through the Niementowski quinazolinone synthesis, named after it’s discoverer Stefan Niementowski. Quinazoline and condensed Quinazoline exhibit potent central nervous system (CNS) activities like anti-anxiety, analgesic, anti-inflammatory [10] and anticonvulsant [11]. Quinazolin-4-ones with 2, 3-disubstitution is reported to possess significant analgesic, anti-inflammatory and anticonvulsant activities Methods: To expand these views and application profiles, efforts have been developed for the synthesis of a new class of quinazolinone by incorporating different amines into synthesized benzoxazinone ring by replacing O atom in the ring. Up to now, a great number of various procedures have been proposed for the synthesis of quinazolin-4-ones in the past few years [16]. Using microwave radiation, this reaction could be easily and rapidly performed in very good yields, providing a large quantity of various 3-substituted-2- propyl-quinazolin-4-one derivatives which can be employed as useful bioactive compounds. We report a facile and efficient method for the synthesis of 3-substituted-2-propyl-quinazolin-4-one by the condensation reaction of Anthranilic acid or Halogen substituted anthranilic acid or methyl anthranilate, butanoic anhydride with various amines. we also reports a drug/ligand or receptor/protein interactions by identifying the suitable active sites in human gamma-aminobutyric acid receptor, the gaba (a)r-beta3 homopentamer human gamma-aminobutyric acid receptor, the gaba (a)r-beta3 homopentamer protein. Results: We are pleased to find that the reaction provided of 3-alkyl/aryl-2-alkyl-quinazolin-4-one gives good yield as well as good quality of product by using MW. All the synthesized compounds were subjected to grid-based molecular docking studies. The results shows that compound 4t have good affinity to the active site residue of human gamma-aminobutyric acid receptor, the gaba (a)r-beta3 homopentamer. Conclusion: The Microwave irradiation for synthesis of the title compounds offers reduction in reaction time, operation simplicity, cleaner reaction, easy work up and improved yields. The procedure clearly highlights the advantages of Green Chemistry. The data reported in this article may be a helpful guide for the medicinal chemists who are working in this area. The Protein-Ligand interaction plays a significant role in structural based drug designing. In the Present work we have docked the ligand, 2, 3-disubstituted quinazolinone with the proteins that are used as the target for GABA-A receptor.

Novel 3-Substituted-2, 3-Dihydro-2-Thioxoquinazolin-4-(1H)-one derivative as Anticonvulsants: Synthesis, Molecular Docking and Pharmacological Screening

2020 ◽  
Vol 17 (6) ◽  
pp. 757-771 ◽  
Author(s):  
Nimisha jain ◽  
Pradeep Kumar Singour
Keyword(s):  
Molecular Docking ◽  
Anticonvulsant Activity ◽  
Type A ◽  
Docking Study ◽  
Aminobutyric Acid ◽  
World Health ◽  
Maximal Electroshock ◽  
Gamma Aminobutyric Acid ◽  
Molecular Docking Study ◽  
Acid Type

Background: According to the World Health Organization, 50 million people worldwide are suffering from epilepsy, making it one of the most common neurological diseases globally. 2,3 disubstituted quinazolinone-4-one derivatives endowed with various pharmacological activity, particularly having anticonvulsant action. Objectives: The aim of this study was to synthesize 3-Substituted-2,3-Dihydro-2-thioxoquinazolin- 4-(1H)-one derivative and evaluate for anticonvulsant activity and neurotoxicity in order to find an efficient, compound with lesser side effects. Methods: A novel series of 3-[4-(2-amino-5, 6-dihydro-4(substituted phenyl)-4H-1, 3-oxazin /thiazin-6yl) phenyl]-2, 3-dihyro-2-thioxoquinazolin-4(1H)-one derivatives (4a-4p) were synthesized. The structures of the synthesized compounds were assigned on the basis of spectral data (UV, IR, 1HNMR, 13CNMR and MS) and performed anticonvulsant activity against maximal electroshock test and Subcutaneous Pentylenetetrazole model. Neurotoxicity was assessed using a rotarod apparatus test. The molecular docking study was performed to assess their binding affinities towards Gamma-Aminobutyric Acid type A receptor. A quantitative estimate of drug-likeness was also performed, which calculates the molecular properties and screen the molecules based on drug-likeness rules. Results: Compounds 4b, 4e, 4j and 4m have shown the highest anticonvulsant activity against tonic seizure with decreased mean duration of tonic hind leg extension of 8.31, 7.35, 8.61 and 8.99 s, respectively in maximal electroshock model and increased onset time clonic convulsion duration of 94.45, 96.65, 93.51 and 91.86 s in Subcutaneous Pentylenetetrazole model. Molecular docking study revealed a better binding affinity with Gamma-Aminobutyric Acid type A receptor. Conclusion: The compound 4b and 4e emerged out as the pilot molecule with a better anticonvulsant activity without any neurotoxicity. The obtained results showed that compounds 4b and 4e could be useful as a template for future design, optimization, and investigation to produce more active analogs.

scholarly journals Synthesis, anti-tubercular evaluation and molecular docking studies of Nitrogen-rich piperazine-pyrimidine-pyrazole Hybrid Motifs

2022 ◽  
Vol 11 (1) ◽  
pp. 95-104
Author(s):  
Bhavinkumar Vavaiya ◽  
Shivani Patel ◽  
Vrajlal Pansuriya ◽  
Vanita Marvaniya ◽  
Popatbhai Patel
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
In Silico ◽  
Docking Studies ◽  
In Vitro Studies ◽  
Coupling Reactions ◽  
Efficient Synthesis ◽  
Docking Score ◽  
Methylene Group

A convenient and efficient synthesis of a series of ethyl-1-(6-(4-substitutedacetylatedpiperazin-1-yl)pyrimidin-4-yl)-5-amino-1H-pyrazole-4-carboxylate (8a-8j) has been developed by five steps which include activation of a methylene group, hydrazinolysis, cyclisation and chloro-amine coupling reactions. Moreover, our proposed mechanism was confirmed in this study demonstrating that ethyl 5-amino-1-(6-chloropyrimidin-4-yl)-1H-pyrazole-4-carboxylate is the key intermediate to fulfill the desired outcomes. In silico and in vitro studies were carried out to identify the active agents among the developed adducts against mycobacterium tuberculosis (PDB ID:4TRO). Compound 8a (Docking Score: -26.81 and MIC: 1.6 ug/mL) was found to be the most potent among the synthesized molecules. All the synthesized compounds showed acceptable drug-like properties which make them suitable for further lead modification using in silico design approaches.

Thiazolidine-2, 4-Diones as Non-Hepatotoxic Tri-action Drug Candidates: Design, Synthesis, Characterization, Biological Evaluation and Docking Studies

2020 ◽  
Vol 17 (9) ◽  
pp. 659-679
Author(s):  
Karuna S. Shukla ◽  
Shailendra Pandey ◽  
Pooja A. Chawla
Keyword(s):  
Antioxidant Activity ◽  
Molecular Docking ◽  
Benzoic Acid ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Standard Drug ◽  
Peripheral Tissues ◽  
Docking Score ◽  
Dpph Method

Thiazolidine-2, 4-diones and their derivatives are a well-established chemical class of compounds that express their pharmacological actions through insulin sensitization and enhanced glucose utilization in peripheral tissues. In the current research different approaches have been employed to synthesize thiazolidine-2, 4-dione derivatives and these synthesized compounds were chemically characterized for the establishment of their chemical structures. A series of thiazolidine-2, 4-dione (TZD) derivatives, Scheme 1 (3A-3V) 22 compounds, were synthesized and characterized by FT-IR, 1H NMR and mass spectral analysis. The title compounds were screened for their in vitro and in vivo antidiabetic, antioxidant, and cytotoxicity studies. In vivo antihyperglycemic effect was assessed by measuring plasma glucose (PG) levels in alloxan-induced type II diabetic rat models. The synthesized TZD derivatives were evaluated for hepatotoxicity and pancreatic tissue integrity. Antioxidant activity was evaluated by the DPPH method and H2O2 method. Thiazolidinedione derivatives were subjected to predict free energy of binding towards target PPARγ, using rosiglitazone as the reference compound for molecular docking visualization through the FlexX docking program. Molecular docking studies are also performed for understanding the binding of a ligand to a receptor. The compound 3V 4-(5- (naphthalen-1-ylmethylene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better blood glucoselowering activity than that of the standard drug rosiglitazone. Compound 3T and 3U exhibited potent antioxidant activity. Among the tested compounds for cytotoxicity using an MTT assay, compound 3H 5-(4-chlorobenzylidene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better viability and cytotoxicity activity. From selected anti-diabetic targets, the proposed derivatives exhibited better interaction with PPARγ receptor, for example, while rosiglitazone showed a docking score of -19.891 kJ/mol, compound 3V exhibited highest docking score of -31.6617 kJ/mol. Computational molecular docking study demonstrated the selectivity and provided a binding model for the further refinement of this chemotype. Therefore, this series of thiazolidine-2, 4-diones derivatives (3A-3V) have considerable importance for development as a potential antihyperglycemic and hypolipidemic agents.

scholarly journals Tropinone-Derived Alkaloids as Potent Anticancer Agents: Synthesis, Tyrosinase Inhibition, Mechanism of Action, DFT Calculation, and Molecular Docking Studies

2020 ◽  
Vol 21 (23) ◽  
pp. 9050
Author(s):  
Katarzyna Piechowska ◽  
Magdalena Mizerska-Kowalska ◽  
Barbara Zdzisińska ◽  
Joanna Cytarska ◽  
Angelika Baranowska-Łączkowska ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cancer Cells ◽  
Cell Lines ◽  
Mechanism Of Action ◽  
Anticancer Agents ◽  
Docking Studies ◽  
Breast Adenocarcinoma ◽  
Inhibition Mechanism ◽  
Molecular Docking Studies ◽  
Rpmi 8226

A new series of hybrid compounds with tropinone and thiazole rings in the structure was designed and synthesized as potential anticancer agents. They were tested against human multiple myeloma (RPMI 8226), lung carcinoma (A549), breast adenocarcinoma (MDA-MB-231), and mouse skin melanoma (B16-F10) cell lines. Toxicity was tested on human normal skin fibroblasts (HSF) and normal colon fibroblasts (CCD-18Co). The growth inhibition mechanism of the most active derivative was analyzed through investigation of its effect on the distribution of cell cycle phases and ability to induce apoptosis and necrosis in RPMI 8226 and A549 cancer cells. The tyrosinase inhibitory potential was assessed, followed by molecular docking studies. Compounds 3a–3h show high anticancer activity against MDA-MB-231 and B16-F10 cell lines with IC50 values of 1.51–3.03 µM. Moreover, the cytotoxic activity of the investigated compounds against HSF and CCD-18Co cells was 8–70 times lower than against the cancer cells or no toxicity was shown in our tests, with derivative 3a being particularly successful. The mechanism of action of compound 3a in RPMI 8226 cell was shown to be through induction of cell death through apoptosis. The derivatives show ability to inhibit the tyrosinase activity with a mixed mechanism of inhibition. The final molecular docking results showed for IC50 distinct correlation with experiment.

Role of catechins on ET-1-induced stimulation of PLD and NADPH oxidase activities in pulmonary smooth muscle cells: determination of the probable mechanism by molecular docking studies

2018 ◽  
Vol 96 (4) ◽  
pp. 417-432 ◽  
Author(s):  
Sajal Chakraborti ◽  
Jaganmay Sarkar ◽  
Rajabrata Bhuyan ◽  
Tapati Chakraborti
Keyword(s):  
Smooth Muscle ◽  
Molecular Docking ◽  
Nadph Oxidase ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Docking Studies ◽  
Oxidase Inhibitor ◽  
Probable Mechanism ◽  
Human Pulmonary Artery ◽  
Stimulation Of

The treatment of human pulmonary artery smooth muscle cells with ET-1 stimulates the activity of PLD and NADPH oxidase, but this stimulation is inhibited by pretreatment with bosentan (ET-1 receptor antagonist), FIPI (PLD inhibitor), apocynin (NADPH oxidase inhibitor), and EGCG and ECG (catechins having a galloyl group), but not EGC and EC (catechins devoid of a galloyl group). Herein, using molecular docking analyses based on our biochemical studies, we determined the probable mechanism by which the catechins containing a galloyl group inhibit the stimulation of PLD activity induced by ET-1. The ET-1-induced stimulation of PLD activity was inhibited by SecinH3 (inhibitor of cytohesin). Arf6 and cytohesin-1 are associated in the cell membrane, which is not inhibited by the catechins during ET-1 treatment of the cells. However, EGCG and ECG inhibited the binding of GTPγS with Arf6, even in the presence of cytohesin-1. The molecular docking analyses revealed that the catechins containing a galloyl group (EGCG and ECG) with cytohesin-1–Arf6GDP, but not the catechins without a galloyl group (EGC and EC), prevent GDP–GTP exchange in Arf6, which seems to be an important mechanism for inhibiting the activation of PLD induced by ET-1, and subsequently increases the activity of NADPH oxidase.

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