Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids

Hegazy, Gehan H.; Ali, Hamed I.

doi:10.1016/j.bmc.2011.12.030

Cited by 41 publications

(26 citation statements)

References 37 publications

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“…CDX1 enantiomers interact through hydrogen bonds with His90, Leu352, Ser353, Tyr355, and Ala527, also involved in the binding of known anti-inflammatory compounds to COX-2 [48,49,50]. CDX1 enantiomers bind similarly to COX-2 binding pocket, with the xanthone scaffold aligned approximately in the same special position, with a slightly different orientation of the aromatic ring and OH group of the chiral moiety (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

et al. 2017

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Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed.

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Section: Resultsmentioning

confidence: 99%

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

et al. 2017

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“…The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 5:1 to 4:1, v/v) to afford 258 mg (80%) of the title compound as a white solid. 1 N-(4-Ethyl-2-vinylphenyl)-2-iodo-5-methoxy-N-methylbenzamide (29). This compound was prepared from 28 by means of GP5 as a yellow oil (78%).…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Transrepression-Selective Liver X Receptor (LXR) Ligands with 5,11-Dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one Skeleton

et al. 2012

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To obtain novel transrepression-selective liver X receptor (LXR) ligands, we adopted a strategy of reducing the transactivational agonistic activity of the 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one derivative 10, which exhibits LXR-mediated transrepressional and transactivational activity. Structural modification of 10 based on the reported X-ray crystal structure of the LXR ligand-binding domain led to a series of compounds, of which almost all exhibited transrepressional activity at 1 or 10 μM but showed no transactivational activity even at 30 μM. Among the compounds obtained, 18 and 22 were confirmed to have LXR-dependent transrepressional activity by using peritoneal macrophages from wild-type and LXR-null mice. A newly developed fluorescence polarization assay indicated that they bind directly to LXRα. Next, further structural modification was performed with the guidance of docking simulations with LXRα, focusing on enhancing the binding of the ligands with LXRα through the introduction of substituents or heteroatom(s). Among the compounds synthesized, compound 48, bearing a hydroxyl group, showed potent, selective, and dose-dependent transrepressional activity.

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“…We discussed the interactions with the residues located in the regions that are relevant to the selectivity towards both isoforms: the Lateral Pocket (LP: Ala527, Leu531, Ser530 & Val349), Constriction Channel (CC: Arg120, Glu524 & Tyr355), Lipophilic Pocket (LiP: Val523), and with Arg513 & His90 [42,43]. We compared the interactions of Table 5).…”

Section: Molecular Dockingmentioning

confidence: 99%

In silico receptor-based drug design of X,Y-benzenesulfonamide derivatives as selective COX-2 inhibitors

Pérez

Sarabia

Villanueva-García

et al. 2016

Comptes Rendus. Chimie

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a b s t r a c tCOX-2 is a widely studied biological target, since its activity is directly related to the inflammation response. The design of COX-2 selective inhibitors is an ongoing topic in drug design. We performed a quantitative structureeactivity relationship and docking studies over a series of benzenesulfonamide derivatives on their inhibition towards COX-1 and COX-2, in order to rationalize their selectivity towards COX-2. Constitutional, topological and molecular property descriptors for the QSAR models and molecular docking calculations were employed. The mathematical model highlighted that lipophilic character and size are the most important features for COX-2 inhibition by benzenesulfonamides. A second QSAR model revealed that the dipole moment, the number of hydrogen bond donors and lipophilicity descriptors of benzenesulfonamides are crucial for their binding to COX-1. Moreover, artificial neural networks were employed to improve the prediction power of the COX-1 inhibition QSAR model. In this sense, we proposed new selective potential inhibitors by introducing different halogens into the benzenesulfonamide scaffold, improving their interactions with key residues of COX-2.

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Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids

Cited by 41 publications

References 37 publications

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

Design, Synthesis, and Biological Evaluation of Novel Transrepression-Selective Liver X Receptor (LXR) Ligands with 5,11-Dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one Skeleton

In silico receptor-based drug design of X,Y-benzenesulfonamide derivatives as selective COX-2 inhibitors

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