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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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    0488993 - ÚEB 2019 RIV DE eng J - Článek v odborném periodiku
    Lamie, P.F. - Philoppes, J.N. - Rárová, Lucie
    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.
    Archiv der Pharmazie. Roč. 351, 3-4 (2018), č. článku e1700311. ISSN 0365-6233
    Grant CEP: GA MŠk(CZ) LO1204
    Institucionální podpora: RVO:61389030
    Klíčová slova: anti-inflammatory * cytotoxicity * diaryl imidazolone derivatives * molecular docking study
    Kód oboru RIV: EB - Genetika a molekulární biologie
    Obor OECD: Biochemical research methods
    Impakt faktor: 2.145, rok: 2018

    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 CO of the oxazolone moiety was responsible for the binding to amino acids inside the LOX active site.
    Trvalý link: http://hdl.handle.net/11104/0283488
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