Design, synthesis, and biological evaluation of 1-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives as ant
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02616-2
ORIGINAL RESEARCH
Design, synthesis, and biological evaluation of 1-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives as anticancer agents Ayoub Aghcheli1 Mahsa Toolabi2 Adileh Ayati3 Setareh Moghimi3 Loghman Firoozpour3 Tayebeh Oghabi Bakhshaiesh4 Elahe Nazeri4 Maryam Norouzbahari5 Rezvan Esmaeili4 Alireza Foroumadi ●
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Received: 18 May 2020 / Accepted: 13 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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-diF substituted derivatives (5d, 5g, and 5k) showed promising activities, especially against Hela cancer cells (IC50 = 0.37, 0.73 and 0.95 µM, respectively) which were significantly more potent than sorafenib as the reference drug (IC50 = 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. Keywords 1,3,4-Thiadiazole Anticancer Sorafenib Cytotoxic activity ●
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Introduction
Supplementary information The online version of this article (https:// doi.org/10.1007/s00044-020-02616-2) contains supplementary material, which is available to authorized users. * Rezvan Esmaeili [email protected] * Alireza Foroumadi [email protected] 1
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
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Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
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Faculty of Medicine, Eastern Mediterranean University, Famagusta, TRNC, via Mersin 10, Turkey
Cancer is a serious risk of human health, caused by dysregulation of normal cell proliferation, currently known as the second leading cause of death in the world (Elmetwally et al. 2019; Elzahabi et al. 2018). Despite the rapid progress made in diagnosis and treatment, cancer therapy represents one of the greatest medical challenges. Multiple therapeutic strategies including surgery, radiotherapy, and chemotherapy have been used in cancer treatment, amongst chemotherapeutic agents are known as the basic approa
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