Synthesis, biological activity and molecular modeling studies of novel COX-1 inhibitors

Martić, Miljen; Tatić, Iva; Marković, Stribor; Koštrun, Sanja

doi:10.1016/j.ejmech.2003.11.011

Cited by 9 publications

(4 citation statements)

References 15 publications

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“…The flexibility of the COXIB scaffold in the gas phase and implicit solvent shown, herein, can be an important characteristic of the COXIB ligands. It has been shown that the binding sites of the COX enzymes are flexible, and the kinetic analysis of COX inhibition suggests multiple binding modes exist within the enzymes27, 37–40. This is also apparent on examination of the COXIB‐COX‐2 complex Figure 6.…”

Section: Resultsmentioning

confidence: 92%

Conformational and thermodynamic analysis of the COXIB scaffold using quantum chemical calculations

Owen

́ri

Jójárt

et al. 2011

Int J of Quantum Chemistry

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Selective cyclo-oxygenase-2 inhibitors (COXIBs) are prominent members of the nonsteroidal anti-inflammatory drugs. The neutral and protonated COXIB scaffold has been subjected to molecular computations in the gas phase and implicit solvent to measure the relative changes in the thermodynamic functions, enthalpy (H rel ), potential energy (U rel ), Gibbs free energy (G rel ) and entropy (S rel ) induced by selected substituents. Conformational analysis of the COXIB scaffold indentified four pairs of atropisomeric conformers (from I, I 0 to IV, IV 0 ) associated with a molecular structure containing a double rotor system. All conformers had similar stability. Para-substitution with substituents that cover a wide range of Hammett sigma values did not alter the geometries of the neutral COXIB conformers; however, the protonated COXIB scaffold was showed an increase in structural and thermodynamic perturbations due to inductive effects. Flexibility and structural resilience of the COXIB scaffold under the conditions studied herein could be an important feature of the COXIBs, especially considering the previously proposed flexibility of the cyclo-oxygenase binding site.

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Section: Resultsmentioning

confidence: 92%

Conformational and thermodynamic analysis of the COXIB scaffold using quantum chemical calculations

Owen

́ri

Jójárt

et al. 2011

Int J of Quantum Chemistry

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“…Various derivatives of ibuprofen moiety into a variety of heterocyclic analogs are reported. For example, 1,3,4-oxadiazoles, [42][43][44] 1,3, 4-thiadiazoles, [45,46] 1,2,4-triazine, [47] 1,2,4-triazole, [48] 1,3-thiazolidine-4one, [49] benzimidazole, [50] imidazopyrazine, [51] heteroatomic amines and amides, [52,53] furoxan, [54,55] polyethylene glycol (PEG), [56] poly(oxyethylene), [57] 1,1-di-(3-carboxyphenyl)ethane derivatives, [58] biodegradable polyesters, [59] and Schiff and Mannich bases. [60] The activity of ibuprofen itself was evaluated to control Staphylococcus aureus biofilms, [61] and its derivatives (hybridized with H 2 S-or NO-donating moieties) were investigated for anti-inflammatory and ulcerogenic potential.…”

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confidence: 99%

Exploring ibuprofen derivatives as α‐glucosidase and lipoxygenase inhibitors: Cytotoxicity and in silico studies

Daud

Abid

Sardar

et al. 2022

Archiv der Pharmazie

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This study reports the synthesis of a series of ibuprofen derivatives, including thiosemicarbazides 4a-f, 1,3,4-oxadiazoles 5a-f, 1,3,4-thiadiazoles 6a-f, 1,2,4triazoles 7a-f, and their S-alkylated derivatives 8a-d. All of the newly synthesized derivatives were analyzed using 1 H NMR, 13 C NMR spectroscopy, and highresolution mass spectra (electron ionization) spectrometry. These synthetic molecules were examined for their in vitro baking yeast α-glucosidase and soybean 15-lipoxygenase (15-LOX) inhibition and cell viability studies. The results revealed that the compounds N-(3,4-dichlorophenyl)−5-[1-(4-isobutylphenyl)ethyl]-1,3,4oxadiazol-2-amine 5f (IC 50 3.05 ± 1.23 µM) and N-(3-fluorophenyl)-5-[1-(4isobutylphenyl)ethyl]-1,3,4-oxadiazol-2-amine 5b (IC 50 3.12 ± 1.21 µM) were the most potent with respect to the α-glucosidase enzyme while in case of 15-LOX, the compound 4-(2,4-dichlorophenyl)-1-[2-(4-isobutylphenyl)propanoyl]thiosemicarbazide 4e showed potent inhibition with an IC 50 value of 55.41 ± 0.41 µM. All these compounds were found least toxic by displaying a blood mononuclear cell viability value of 69.2%-97.8% by the MTT assay compared to the standards when assayed at 0.25 mM concentration. Molecular docking analyses were conducted to evaluate the inhibition profiles of these derivatives against the said enzymes and the data supported the in vitro profiles.

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“…Docking calculations alone or combined with the virtual screening has been carried out to develop the DHFR and tyrosine kinase inhibitors etc [2][3][4][5][6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

In Silico Screening, Synthesis and In Vitro Evaluation of Some Quinazolinone and Pyridine Derivatives as Dihydrofolate Reductase Inhibitors for Anticancer Activity

Nerkar

Saxena

Ghone

et al. 2009

Journal of Chemistry

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Dihydrofolate reductase (DHFR) is the important target for anticancer drugs belonging to the class of antimetabolites as the enzyme plays important role in the de novo purine synthesis. We here report the in silico screening to obtain best fit molecules as DHFR inhibitors, synthesis of some 'best fit' quinazolinone from 2-phenyl-3-(substituted-benzilidine-amino) quinazolinones (Quinazolinone Shiff's bases) QSB 1-5 and pyridine-4-carbohydrazide Shiff's bases (ISB 1-5 ) derivatives and their in vitro anticancer assay. Synthesis of the molecules was performed using microwave assisted synthesis. The structures of these molecules were elucidated by IR and 1 H-NMR. These compounds were then subjected for in vitro anticancer evaluation against five human cancer cell-lines for anticancer cyto-toxicity assay. Methotrexate (MTX) was used as standard for this evaluation to give a comparable inhibition of the cell proliferation by DHFR inhibition. Placlitaxel, adriamycin and 5-fluoro-uracil were also used as standard to give a comparable activity of these compounds with other mechanism of anticancer activity. ISB 3 (4-(N, N-dimethyl-amino)-phenyl) Schiff's base derivative of pyridine carbohydrazide showed equipotent activity with the standards used in in vitro anticancer assay as per the NCI (National Cancer Institute) guidelines.

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Synthesis, biological activity and molecular modeling studies of novel COX-1 inhibitors

Cited by 9 publications

References 15 publications

Conformational and thermodynamic analysis of the COXIB scaffold using quantum chemical calculations

Conformational and thermodynamic analysis of the COXIB scaffold using quantum chemical calculations

Exploring ibuprofen derivatives as α‐glucosidase and lipoxygenase inhibitors: Cytotoxicity and in silico studies

In Silico Screening, Synthesis and In Vitro Evaluation of Some Quinazolinone and Pyridine Derivatives as Dihydrofolate Reductase Inhibitors for Anticancer Activity

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