期刊
BIOORGANIC CHEMISTRY
卷 91, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.103132
关键词
Anti-inflammatory; Pyrazole; Thiohydantoin; Cyclooxygenase; Anti-cancer screening; Topoisomerase-1 inhibitors
A new series of hybrid structures 14a-l containing thiohydantoin as anti-cancer moiety and pyrazole core possessing SO2Me pharmacophore as selective COX-2 moiety was designed and synthesized to be evaluated for both anti-inflammatory and anti-cancer activities. The synthesized compounds were evaluated for their COX inhibition, in vivo anti-inflammatory activity, ulcerogenic liability, in vitro cytotoxic activity and human topoisomerase-1 inhibition. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Also, all derivatives were significantly less ulcerogenic (ulcer indexes = 2.64-3.87) than ibuprofen (ulcer index = 20.25) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer index = 2.99). Regarding anti-cancer activity, most of the target derivatives showed activities against A-549, MCF-7 and HCT-116 cell lines (IC50 = 5.32-17.90, 3.67-19.04 and 3.19-14.87 mu M respectively) in comparison with doxorubicin (IC50 = 0.20, 0.50 and 2.44 mu M respectively). Compound 14a inhibited the human topoisomerase-1 with IC50 = 29.7 mu g/ml while 14b and 14c showed more potent inhibitory activity with IC50 = 26.5 and 23.3 mu g/ml. respectively in comparison with camptothecin (IC50 = 20.2 mu g/ml). Additionally, COX-2 and human topoisomerase-1 docking studies were carried out to explain the interaction of the synthesized hybrid structures 14a-l with the target enzymes.
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