Synthesis, antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies

El‐Azab, Adel S.; Abdel‐Aziz, Alaa A.‐M.; Abou-Zeid, Laila A.; El-Husseiny, Walaa M.; El_Morsy, Ahmad M.; El-Gendy, Manal A.; El‐Sayed, Magda A.‐A.

doi:10.1080/14756366.2018.1474878

Cited by 30 publications

(7 citation statements)

References 53 publications

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“…Drugs that can act as multi-targeted agents can enhance efficacy and confront chemoresistance exhibited by GB cells. Thioesters has been investigated as an antitumor agent in multiple studies [40,41]. The present study validates potential of a novel orthothioester 5a, as an excellent pharmacological scaffold possessing strong cytotoxic, anti-angiogenic, and chemo-sensitization activity.…”

Section: Discussionsupporting

confidence: 72%

Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect

Viswanathan

Musa

Murugesan

et al. 2019

Cells

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Glioblastoma (GB), a grade IV glioma, with high heterogeneity and chemoresistance, obligates a multidimensional antagonist to debilitate its competence. Considering the previous reports on thioesters as antitumor compounds, this paper investigates on use of this densely functionalized sulphur rich molecule as a potent anti-GB agent. Bio-evaluation of 12 novel compounds, containing α-thioether ketone and orthothioester functionalities, identified that five analogs exhibited better cytotoxic profile compared to standard drug cisplatin. Detailed toxicity studies of top compound were evaluated in two cell lines, using cell viability test, apoptotic activity, oxidative stress and caspase activation and RNA-sequencing analysis, to obtain a comprehensive molecular profile of drug activity. The most effective molecule presented half maximal inhibitory concentration (IC50) values of 27 μM and 23 μM against U87 and LN229 GB cells, respectively. Same compound effectively weakened various angiogenic pathways, mainly MAPK and JAK-STAT pathways, downregulating VEGF. Transcriptome analysis identified significant promotion of apoptotic genes, and genes involved in cell cycle arrest, with concurrent inhibition of various tyrosine kinase cascades and stress response genes. Docking and immunoblotting studies suggest EGFR as a strong target of the orthothioester identified. Therefore, orthothioesters can potentially serve as a multi-dimensional chemotherapeutic possessing strong cytotoxic, anti-angiogenic and chemo-sensitization activity, challenging glioblastoma pathogenesis.

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Section: Discussionsupporting

confidence: 72%

Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect

Viswanathan

Musa

Murugesan

et al. 2019

Cells

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“…We collected 259 COX-2 inhibitors from newly reported work − to build an external test set, which included 44 highly active inhibitors (IC 50 ≤ 0.1 μM) and 215 weakly active inhibitors (IC 50 ≥ 10 μM). All these 259 inhibitors were different from the 2925 inhibitors in data set 1.…”

Section: Materials and Methodsmentioning

confidence: 99%

Classification of Cyclooxygenase-2 Inhibitors Using Support Vector Machine and Random Forest Methods

Qin

Yang

Zhang

et al. 2019

J. Chem. Inf. Model.

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This work reports the classification study conducted on the biggest COX-2 inhibitor data set so far. Using 2925 diverse COX-2 inhibitors collected from 168 pieces of literature, we applied machine learning methods, support vector machine (SVM) and random forest (RF), to develop 12 classification models. The best SVM and RF models resulted in MCC values of 0.73 and 0.72, respectively. The 2925 COX-2 inhibitors were reduced to a data set of 1630 molecules by removing intermediately active inhibitors, and 12 new classification models were constructed, yielding MCC values above 0.72. The best MCC value of the external test set was predicted to be 0.68 by the RF model using ECFP_4 fingerprints. Moreover, the 2925 COX-2 inhibitors were clustered into eight subsets, and the structural features of each subset were investigated. We identified substructures important for activity including halogen, carboxyl, sulfonamide, and methanesulfonyl groups, as well as the aromatic nitrogen atoms. The models developed in this study could serve as useful tools for compound screening prior to lab tests.

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“…But only recently have COXs, notably COX‐1, been connected to a wide range of human illnesses like cancer, heart failure, neurological, and neurodegenerative disorders. The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX‐2 [8] . The active site for COX‐1′s grid formation is thought to be the binding site for the crystal ligand diclofenac [9] .…”

Section: Introductionmentioning

confidence: 99%

Aceclofenac Derivatives: Synthesis, Characterization, and Determination of Anti‐oxidant and Anti‐inflammatory Activities by Chemiluminescence Assays and Molecular Docking Studies

et al. 2023

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Aceclofenac (ACF) is a newer derivative of diclofenac, and one of the emerging NSAIDs for the treatment of various inflammatory diseases. In this research we have develop a set of 2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)acetic acid derivatives (AR1-AR12) using Fischer esterification in good yields and in an efficient manner. All the compounds were fully characterized physical (solubility and melting points) and chemical by spectral data analysis of FTIR, 1 HNMR and 13 CNMR and elemental analysis. In-vitro anti-inflammatory activity was performed by Chemiluminescence technique in which we found2,6-dichlorophenyl)amino)phenyl)acetoxy)acetate) (AR9 76.3 %) found more potent as compared to parent compound while AR3, AR6 and AR9 highly potent than standard reference ibuprofen (73.2 %). The current molecular docking study was performed In order to check the suitable method for the binding of target ligands and proteins Glide docking with extra precision (XP) mode. The hydrogen bonding interactions of Aceclofenac are prominent with Isoleucine moiety, those of compound AR-6 shows hydrophobic interaction with active amino acid Leucine and Phenylalanine moieties. Anti-oxidant activities were also performed, AR-3 (79.30 %), AR-5 (91.23 %), AR-9 (83.43 %) AR-12 (92.43 %) were found to be more anti-oxidant as compared to aceclofenac (ACF) (66.46 %). These derivatives were synthesized with different aliphatic and aromatic alcohols and phenols.

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Synthesis, antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies

Cited by 30 publications

References 53 publications

Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect

Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect

Classification of Cyclooxygenase-2 Inhibitors Using Support Vector Machine and Random Forest Methods

Aceclofenac Derivatives: Synthesis, Characterization, and Determination of Anti‐oxidant and Anti‐inflammatory Activities by Chemiluminescence Assays and Molecular Docking Studies

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