Design, synthesis, and biological evaluation of 1-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives as anticancer agents

A novel series of 1-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives ( 5a–l ) were designed and synthesized as sorafenib analogs. The in vitro cytotoxicity effects of synthesized compounds were evaluated against four different human cancer cells including MCF-7, HepG2, A549, and HeLa...

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Published in:Medicinal chemistry research 2020-11, Vol.29 (11), p.2000-2010
Main Authors: Aghcheli, Ayoub, Toolabi, Mahsa, Ayati, Adileh, Moghimi, Setareh, Firoozpour, Loghman, Bakhshaiesh, Tayebeh Oghabi, Nazeri, Elahe, Norouzbahari, Maryam, Esmaeili, Rezvan, Foroumadi, Alireza
Format: Article
Language:English
Subjects:
Anticancer properties
Antitumor agents
Apoptosis
Biochemistry
Biological effects
Biomedical and Life Sciences
Biomedicine
Bioorganic Chemistry
Cancer
Cell cycle
Cell death
Cell proliferation
Cytotoxicity
Derivatives
Flow cytometry
G1 phase
Inorganic Chemistry
Medicinal Chemistry
Original Research
Pharmacology/Toxicology
Phenylurea
Prototypes
Synthesis
Toxicity
Vascular endothelial growth factor receptors
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Summary:A novel series of 1-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives ( 5a–l ) were designed and synthesized as sorafenib analogs. The in vitro cytotoxicity effects of synthesized compounds were evaluated against four different human cancer cells including MCF-7, HepG2, A549, and HeLa cell lines. The biological results showed that most of the compounds significantly prevented the proliferation of tested cancer cells. In particular, 2-F, 4-Cl, and 2,6- di F substituted derivatives ( 5d , 5g , and 5k ) showed promising activities, especially against Hela cancer cells (IC 50  = 0.37, 0.73 and 0.95 µM, respectively) which were significantly more potent than sorafenib as the reference drug (IC 50  = 7.91 µM). Flow cytometry analysis revealed that the prototype compounds ( 5d , 5g , and 5k ) significantly induced apoptotic cell death in HeLa cancer cells and blocked the cell cycle at the sub-G1 phase. Moreover, in silico docking study confirmed the binding of the prototype compound to the active site of VEGFR-2.
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-020-02616-2