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Design, synthesis, and biological evaluation of novel 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4 H )‐imidazolone derivatives as cytotoxic agents and COX‐2/LOX inhibitors
Author(s) -
Lamie Phoebe F.,
Philoppes John N.,
Rárová Lucie
Publication year - 2018
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201700311
Subject(s) - chemistry , zileuton , stereochemistry , active site , arachidonate 5 lipoxygenase , moiety , cyclooxygenase , isoxazole , biological activity , kojic acid , enzyme , in vitro , biochemistry , tyrosinase , arachidonic acid
A new series of 1,2‐diaryl‐4‐substituted‐benzylidene‐5(4 H )‐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.