scholarly journals Pharmacological Evaluation and Docking Studies of 3-Thiadiazolyl- and Thioxo-1,2,4-triazolylcoumarin Derivatives as Cholinesterase Inhibitors

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ahsan Raza ◽  
Aamer Saeed ◽  
Aliya Ibrar ◽  
Muhammad Muddassar ◽  
Aftab Ahmed Khan ◽  
...  
Keyword(s):  
Cholinesterase Inhibitors ◽  
Horse Serum ◽  
Docking Studies ◽  
Site Structure ◽  
Electrophorus Electricus ◽  
Promising Strategy ◽  
Structure Activity ◽  
Comprehensive Knowledge ◽  
Ellman’S Method ◽  
Micromolar Range

Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is considered a promising strategy for the treatment of Alzheimer’s disease (AD). This research project aims to provide a comprehensive knowledge of newly synthesized coumarin analogues with anti-AD potential. In the present work a series of 3-thiadiazolyl- and thioxo-1,2,4-triazolylcoumarins derivatives were designed, synthesized, and tested as potent inhibitors of cholinesterases. These compounds were assayed against AChE from electrophorus electricus and rabbit; and BChE from horse serum and rabbit by Ellman’s method using neostigmine methylsulphate and donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors of AChE and BChE with Ki values in the micromolar range. 4b was found to be the most active compound with Ki value 0.028±0.002 μM and higher selectivity for AChE/BChE. The ability of 4b to interact with AChE was further confirmed through computational studies, in which a primary binding was proved to occur at the active gorge site, and a secondary binding was revealed at the peripheral anionic site. Structure activity relationships of prepared compounds were also discussed.

scholarly journals Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases

2020 ◽  
Vol 21 (21) ◽  
pp. 8088
Author(s):  
Antonio Zandona ◽  
Gabriela Lihtar ◽  
Nikola Maraković ◽  
Katarina Miš ◽  
Valentina Bušić ◽  
...  
Keyword(s):  
Active Site ◽  
Cholinesterase Inhibitors ◽  
Potent Inhibitor ◽  
Docking Studies ◽  
Biologically Active ◽  
Active Site Residues ◽  
Vitamin B3 ◽  
Starting Point ◽  
Novel Drugs ◽  
Micromolar Range

We evaluated the potential of nine vitamin B3 scaffold-based derivatives as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, as a starting point for the development of novel drugs for treating disorders with cholinergic neurotransmission-linked pathology. As the results indicate, all compounds reversibly inhibited both enzymes in the micromolar range pointing to the preference of AChE over BChE for binding the tested derivatives. Molecular docking studies revealed the importance of interactions with AChE active site residues Tyr337 and Tyr124, which dictated most of the observed differences. The most potent inhibitor of both enzymes with Ki of 4 μM for AChE and 8 μM for BChE was the nicotinamide derivative 1-(4′-phenylphenacyl)-3-carbamoylpyridinium bromide. Such a result places it within the range of several currently studied novel cholinesterase inhibitors. Cytotoxicity profiling did not classify this compound as highly toxic, but the induced effects on cells should not be neglected in any future detailed studies and when considering this scaffold for drug development.

Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors

2020 ◽  
Vol 20 (23) ◽  
pp. 2106-2117
Author(s):  
Martin Krátký ◽  
Šárka Štěpánková ◽  
Michaela Brablíková ◽  
Katarína Svrčková ◽  
Markéta Švarcová ◽  
...  
Keyword(s):  
Biological Activities ◽  
Structural Parameters ◽  
Covalent Binding ◽  
Docking Studies ◽  
Potent Inhibition ◽  
Brain Barrier Permeability ◽  
Electric Eel ◽  
Ic50 Values ◽  
Ellman’S Method

Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment. Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery. Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

Development of Novel Glitazones as Antidiabetic Agents: Molecular Design, Synthesis, Evaluation of Glucose Uptake Activity and SAR Studies

2020 ◽  
Vol 17 (7) ◽  
pp. 840-849
Author(s):  
Mahendra Gowdru Srinivas ◽  
Prabitha Prabhakaran ◽  
Subhankar Probhat Mandal ◽  
Yuvaraj Sivamani ◽  
Pranesh Guddur ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Molecular Design ◽  
Docking Studies ◽  
Antidiabetic Activity ◽  
Design Synthesis ◽  
In Silico Docking ◽  
Ppar Γ ◽  
Sar Studies ◽  
Structure Activity ◽  
Uptake Activity

Background: Thiazolidinediones and its bioisostere, namely, rhodanines have become ubiquitous class of heterocyclic compounds in drug design and discovery. In the present study, as part of molecular design, a series of novel glitazones that are feasible to synthesize in our laboratory were subjected to docking studies against PPAR-γ receptor for their selection. Methods and Results: As part of the synthesis of selected twelve glitazones, the core moiety, pyridine incorporated rhodanine was synthesized via dithiocarbamate. Later, a series of glitazones were prepared via Knovenageal condensation. In silico docking studies were performed against PPARγ protein (2PRG). The titled compounds were investigated for their cytotoxic activity against 3T3-L1 cells to identify the cytotoxicity window of the glitazones. Further, within the cytotoxicity window, glitazones were screened for glucose uptake activity against L6 cells to assess their possible antidiabetic activity. Conclusion: Based on the glucose uptake results, structure activity relationships are drawn for the title compounds.

Towards further Understanding the Structural Requirements of Combretastatin- like Chalcones as Inhibitors of Microtubule Polymerization

2020 ◽  
Vol 16 (2) ◽  
pp. 155-166
Author(s):  
Naveen Dhingra ◽  
Anand Kar ◽  
Rajesh Sharma
Keyword(s):  
Three Dimensional ◽  
3D Qsar ◽  
Docking Study ◽  
Structure Activity Relationship ◽  
Docking Studies ◽  
Activity Relationship ◽  
Structural Requirement ◽  
Ligand Interaction ◽  
Microtubule Polymerization ◽  
Structure Activity

Background: Microtubules are dynamic filamentous cytoskeletal structures which play several key roles in cell proliferation and trafficking. They are supposed to contribute in the development of important therapeutic targeting tumor cells. Chalcones are important group of natural compounds abundantly found in fruits & vegetables that are known to possess anticancer activity. We have used QSAR and docking studies to understand the structural requirement of chalcones for understanding the mechanism of microtubule polymerization inhibition. Methods: Three dimensional (3D) QSAR (CoMFA and CoMSIA), pharmacophore mapping and molecular docking studies were performed for the generation of structure activity relationship of combretastatin-like chalcones through statistical models and contour maps. Results: Structure activity relationship revealed that substitution of electrostatic, steric and donor groups may enhance the biological activity of compounds as inhibitors of microtubule polymerization. From the docking study, it was clear that compounds bind at the active site of tubulin protein. Conclusion: The given strategies of modelling could be an encouraging way for designing more potent compounds as well as for the elucidation of protein-ligand interaction.

Recent Development of Sulfonyl or Sulfonamide Hybrids as Potential Anticancer Agents: A Key Review

2018 ◽  
Vol 18 (4) ◽  
pp. 488-505 ◽  
Author(s):  
K. P. Rakesh ◽  
Shi-Meng Wang ◽  
Jing Leng ◽  
L. Ravindar ◽  
Abdullah M. Asiri ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Anticancer Agents ◽  
Side Effect ◽  
Docking Studies ◽  
Multi Drug Resistance ◽  
Anticancer Activities ◽  
Pharmacological Activities ◽  
Synthetic Compounds ◽  
Structure Activity ◽  
Anticancer Drug Discovery

Cancer is the second leading cause of death worldwide. There is always a huge demand for novel anticancer drugs and diverse new natural or synthetic compounds are developed continuously by scientists. Presently, a large number of drugs in clinical practice have showed pervasive side effect and multidrug resistance. Sulfonyl or sulfonamide hybrids became one of the most attractive subjects due to their broad spectrum of pharmacological activities. Sulfonyl hybrids were broadly explored for their anticancer activities and it was found that they possess minimum side effect along with multi-drug resistance activity. This review describes the most recent applications of sulfonyl hybrid analogues in anticancer drug discovery and further discusses the mechanistic insights, structure-activity relationships and molecular docking studies for the potent derivatives.

Evaluation of Cytotoxic and Tyrosinase Inhibitory Activities of 2-phenoxy(thiomethyl) pyridotriazolopyrimidines: In Vitro and Molecular Docking Studies

2020 ◽  
Vol 20 (14) ◽  
pp. 1714-1721
Author(s):  
Hatem A. Abuelizz ◽  
El Hassane Anouar ◽  
Mohamed Marzouk ◽  
Mizaton H. Hasan ◽  
Siti R. Saleh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Kojic Acid ◽  
Docking Studies ◽  
Breast Adenocarcinoma ◽  
Amino Acid Residues ◽  
New Class ◽  
Structure Activity ◽  
Tyrosinase Inhibitors ◽  
Mcf 7

Background: The use of tyrosinase has confirmed to be the best means of recognizing safe, effective, and potent tyrosinase inhibitors for whitening skin. Twenty-four 2-phenoxy(thiomethyl)pyridotriazolopyrimidines were synthesized and characterized in our previous studies. Objective: The present work aimed to evaluate their cytotoxicity against HepG2 (hepatocellular carcinoma), A549 (pulmonary adenocarcinoma), MCF-7 (breast adenocarcinoma) and WRL 68 (embryonic liver) cell lines. Methods: MTT assay was employed to investigate the cytotoxicity, and a tyrosinase inhibitor screening kit was used to evaluate the Tyrosinase (TYR) inhibitory activity of the targets. Results: The tested compounds exhibited no considerable cytotoxicity, and nine of them were selected for a tyrosinase inhibitory test. Compounds 2b, 2m, and 5a showed good inhibitory percentages against TYR compared to that of kojic acid (reference substance). Molecular docking was performed to rationalize the Structure-Activity Relationship (SAR) of the target pyridotriazolopyrimidines and analyze the binding between the docked-selected compounds and the amino acid residues in the active site of tyrosinase. Conclusion: The target pyridotriazolopyrimidines were identified as a new class of tyrosinase inhibitors.

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