Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents
Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents
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DOI：
10.1016/j.ejmech.2019.03.008
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Hai-Liang Zhu
中科院分区：
文献类型：
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作者：
Li Zhang;Zhong-Chang Wang;Xin Li;Muhammad Abbas;Song-Yu Wu;Shen-Zhen Ren;Qi-Xing Liu;Li Liu;Peng-Wen Chen;Yong-Tao Duan;Peng-Cheng Lv;Hai-Liang Zhu
In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as.dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of.them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them,.compound A33 displayed the most potency against cancer cell lines (IC50 ¼ 6.43e10.97 mM for F10,.HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50 ¼194.01 mM.vs. celecoxib: IC50 ¼ 97.87 mM for 293T cells), and excellent inhibitory activities on COX-2.(IC50 ¼ 0.17 mM) and 5-LOX (IC50 ¼ 0.68 mM). Meanwhile, the molecular modeling study was performed.to position compound A33 into COX-2 and 5-LOX active sites to determine the probable.binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2.phase and subsequently induced apoptosis of F10 cells. Furthermore, compound A33 could significantly.inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound.A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising.candidate for cancer therapy.
