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Design, synthesis, and biological evaluation of novel 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives as cytotoxic agents and COX-2/LOX inhibitors
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SYSNO ASEP 0488993 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Design, synthesis, and biological evaluation of novel 1,2-diaryl-4-substituted-benzylidene-5(4H)-imidazolone derivatives as cytotoxic agents and COX-2/LOX inhibitors Author(s) Lamie, P.F. (EG)
Philoppes, J.N. (EG)
Rárová, Lucie (UEB-Q) RID, ORCIDNumber of authors 3 Article number e1700311 Source Title Archiv der Pharmazie. - : Wiley - ISSN 0365-6233
Roč. 351, 3-4 (2018)Number of pages 11 s. Language eng - English Country DE - Germany Keywords anti-inflammatory ; cytotoxicity ; diaryl imidazolone derivatives ; molecular docking study Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemical research methods R&D Projects LO1204 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UEB-Q - RVO:61389030 UT WOS 000428990000006 EID SCOPUS 85041582657 DOI 10.1002/ardp.201700311 Annotation 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 IC 50 values (0.25–1.7 µM) were lower than that of indomethacin (IC 50 = 9.47 µM) and somewhat higher than that of celecoxib (IC 50 = 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 IC 50 values of 0.02–74.03 µM, while the IC 50 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. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2019
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