Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9-252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.
- MeSH
- antiflogistika nesteroidní * farmakologie MeSH
- cyklooxygenasa 2 metabolismus MeSH
- inhibitory cyklooxygenasy 2 * farmakologie chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1β and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 μM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.
- MeSH
- acetylcholin nedostatek MeSH
- Alzheimerova nemoc farmakoterapie patologie MeSH
- buněčné linie MeSH
- buňky PC12 MeSH
- cholinesterasové inhibitory chemie MeSH
- inhibitory cyklooxygenasy 2 chemie MeSH
- inhibitory lipoxygenas chemie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- neurony účinky léků enzymologie patologie MeSH
- racionální návrh léčiv MeSH
- semikarbazidy chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- triazoly chemie farmakologie MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A new series of 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives 4a-l was synthesized. Their structures were confirmed by different spectroscopic techniques (IR, 1 H NMR, DEPT-Q NMR, and mass spectroscopy) and elemental analyses. Their cytotoxic activities in vitro were evaluated against breast, ovarian, and liver cancer cell lines and also normal human skin fibroblasts. Cyclooxygenase (COX)-1, COX-2 and lipoxygenase (LOX) inhibitory activities were measured. The synthesized compounds showed selectivity toward COX-2 rather than COX-1, and the IC50 values (0.25-1.7 µM) were lower than that of indomethacin (IC50 = 9.47 µM) and somewhat higher than that of celecoxib (IC50 = 0.071 µM). The selectivity index for COX-2 of the oxazole derivative 4e (SI = 3.67) was nearly equal to that of celecoxib (SI = 3.66). For the LOX inhibitory activity, the new compounds showed IC50 values of 0.02-74.03 µM, while the IC50 of the reference zileuton was 0.83 µM. The most active compound 4c (4-chlorobenzoxazole derivative) was found to have dual COX-2/LOX activity. All the synthesized compounds were docked inside the active site of the COX-2 and LOX enzymes. They linked to COX-2 through the N atom of the azole scaffold, while CO of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.
- MeSH
- antiflogistika nesteroidní chemická syntéza chemie farmakologie MeSH
- arachidonát-5-lipoxygenasa metabolismus MeSH
- cyklooxygenasa 2 metabolismus MeSH
- imidazoly chemická syntéza chemie farmakologie MeSH
- inhibitory cyklooxygenasy 2 chemická syntéza chemie farmakologie MeSH
- inhibitory lipoxygenas chemická syntéza chemie farmakologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- racionální návrh léčiv * MeSH
- simulace molekulového dockingu MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Geranyl flavones have been studied as compounds that potentially can be developed as anti-inflammatory agents. A series of natural geranylated flavanones was isolated from Paulownia tomentosa fruits, and these compounds were studied for their anti-inflammatory activity and possible mechanism of action. Two new compounds were characterized [paulownione C (17) and tomentodiplacone O (20)], and all of the isolated derivatives were assayed for their ability to inhibit cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX). The compounds tested showed variable degrees of activity, with several of them showing activity comparable to or greater than the standards used in COX-1, COX-2, and 5-LOX assays. However, only the compound tomentodiplacone O (20) showed more selectivity against COX-2 versus COX-1 when compared with ibuprofen. The ability of the test compounds to interact with the above-mentioned enzymes was supported by docking studies, which revealed the possible incorporation of selected test substances into the active sites of these enzymes. Furthermore, one of the COX/LOX dual inhibitors, diplacone (14) (a major geranylated flavanone of P. tomentosa), was studied in vitro to obtain a proteomic overview of its effect on inflammation in LPS-treated THP-1 macrophages, supporting its previously observed anti-inflammatory activity and revealing the mechanism of its anti-inflammatory effect.
- MeSH
- antiflogistika chemie izolace a purifikace farmakologie MeSH
- arachidonát-5-lipoxygenasa metabolismus MeSH
- cyklooxygenasa 1 metabolismus MeSH
- cyklooxygenasa 2 metabolismus MeSH
- flavonoidy chemie izolace a purifikace farmakologie MeSH
- inhibitory cyklooxygenasy 2 chemie izolace a purifikace farmakologie MeSH
- inhibitory lipoxygenas chemie izolace a purifikace farmakologie MeSH
- Magnoliopsida chemie MeSH
- molekulární struktura MeSH
- ovoce chemie MeSH
- proteomika * MeSH
- Publikační typ
- časopisecké články MeSH
Two new series of N-substituted indole derivatives 4a-l and 5a-h were synthesized. Their chemical structures were confirmed using spectroscopic tools including IR, (1)H NMR, (13)C NMR mass spectroscopy and elemental analyses. The results showed no significant cytotoxic activity on either cancer or normal human cells. Anti-inflammatory activity for all target compounds was evaluated in vitro. Compounds 5a-h were found to have better anti-inflammatory activity than 4a-l. The inhibitory activity of COX-2 and 5-LOX were tested for 5a-h. Three compounds, 5c, 5d and 5f showed excellent COX-2 inhibitory activity with IC50 ranging from 0.98 to 1.23 μM compared to the reference celecoxib (1.54 μM). These compounds had a reasonable selectivity index between 7.03 and 8.05. Additionally, p-methylbenzoyl derivative 5g (IC50 = 5.78 μM) had superior 5-LOX inhibitory activity, higher than quercetin. 5e was close to quercetin in its LOX inhibitory activity. Compounds 5a-h were docked inside the active site of COX-2 and 5-LOX enzymes.
- MeSH
- antiflogistika chemická syntéza chemie metabolismus farmakologie MeSH
- antitumorózní látky chemická syntéza chemie metabolismus farmakologie MeSH
- arachidonát-5-lipoxygenasa chemie metabolismus MeSH
- cyklooxygenasa 1 metabolismus MeSH
- cyklooxygenasa 2 metabolismus MeSH
- indoly chemická syntéza chemie metabolismus farmakologie MeSH
- inhibitory cyklooxygenasy 2 chemická syntéza chemie metabolismus farmakologie MeSH
- inhibitory lipoxygenas chemická syntéza chemie metabolismus farmakologie MeSH
- katalytická doména MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- racionální návrh léčiv * MeSH
- Schiffovy báze chemie MeSH
- simulace molekulového dockingu * MeSH
- techniky syntetické chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Cudraflavone B (1) is a prenylated flavonoid found in large amounts in the roots of Morus alba, a plant used as a herbal remedy for its reputed anti-inflammatory properties. The present study shows that this compound causes a significant inhibition of inflammatory mediators in selected in vitro models. Thus, 1 was identified as a potent inhibitor of tumor necrosis factor α (TNFα) gene expression and secretion by blocking the translocation of nuclear factor κB (NF-κB) from the cytoplasm to the nucleus in macrophages derived from a THP-1 human monocyte cell line. The NF-κB activity reduction resulted in the inhibition of cyclooxygenase 2 (COX-2) gene expression. Compound 1 acts as a COX-2 and COX-1 inhibitor with higher selectivity toward COX-2 than indomethacin. Pretreatment of cells by 1 shifted the peak in an regulatory gene zinc-finger protein 36 (ZFP36) expression assay. This natural product has noticeable anti-inflammatory properties, suggesting that 1 potentially could be used for development as a nonsteroidal anti-inflammatory drug lead.
- MeSH
- aktiny účinky léků MeSH
- antiflogistika nesteroidní chemie izolace a purifikace farmakologie MeSH
- cyklooxygenasa 1 účinky léků MeSH
- flavonoidy chemie izolace a purifikace farmakologie MeSH
- inhibitory cyklooxygenasy 2 chemie izolace a purifikace farmakologie MeSH
- kořeny rostlin chemie MeSH
- lidé MeSH
- makrofágy účinky léků MeSH
- molekulární struktura MeSH
- Morus chemie MeSH
- NF-kappa B antagonisté a inhibitory MeSH
- TNF-alfa antagonisté a inhibitory genetika MeSH
- tristetraprolin účinky léků genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
