Thiohydantoin derivatives incorporating a pyrazole core: Design,synthesis and biological evaluation as dual inhibitors of topoisomerase-I and cycloxygenase-2 with anti-cancer and anti-inflammatory activities |
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Institution: | 1. Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516 Kafrelsheikh, Egypt;2. Faculty of Education, Shaqra University, Al Muzahimiyah, Shaqra, Riyadh Province, P.O. Box 90, Zip Code 11921, Kingdom Saudi Arabia;3. Theoretical Applied Chemistry Unit (TACU), Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt;4. Chemistry Department, Faculty of Science, Suez Canal University, 41522 Ismailia, Egypt |
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Abstract: | 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 µM respectively) in comparison with doxorubicin (IC50 = 0.20, 0.50 and 2.44 µM respectively). Compound 14a inhibited the human topoisomerase-1 with IC50 = 29.7 µg/ml while 14b and 14c showed more potent inhibitory activity with IC50 = 26.5 and 23.3 µg/ml. respectively in comparison with camptothecin (IC50 = 20.2 µg/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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Keywords: | Anti-inflammatory Pyrazole Thiohydantoin Cyclooxygenase Anti-cancer screening Topoisomerase-1 inhibitors |
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