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.
Bioorg Chem
; 91: 103132, 2019 10.
Article
in En
| MEDLINE
| ID: mdl-31374529
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 indexesâ¯=â¯2.64-3.87) than ibuprofen (ulcer indexâ¯=â¯20.25) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer indexâ¯=â¯2.99). Regarding anti-cancer activity, most of the target derivatives showed activities against A-549, MCF-7 and HCT-116 cell lines (IC50â¯=â¯5.32-17.90, 3.67-19.04 and 3.19-14.87⯵M respectively) in comparison with doxorubicin (IC50â¯=â¯0.20, 0.50 and 2.44⯵M respectively). Compound 14a inhibited the human topoisomerase-1 with IC50â¯=â¯29.7⯵g/ml while 14b and 14c showed more potent inhibitory activity with IC50â¯=â¯26.5 and 23.3⯵g/ml. respectively in comparison with camptothecin (IC50â¯=â¯20.2⯵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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrazoles
/
Thiohydantoins
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Enzyme Inhibitors
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Anti-Inflammatory Agents
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Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
Bioorg Chem
Year:
2019
Document type:
Article