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Design, synthesis, and molecular docking of novel indole scaffold‐based VEGFR‐2 inhibitors as targeted anticancer agents
Author(s) -
Roaiah Hanaa M.,
Ghannam Iman A. Y.,
Ali Islam H.,
El Kerdawy Ahmed M.,
Ali Mamdouh M.,
Abbas Safinaz ES.,
ElNakkady Sally S.
Publication year - 2018
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201700299
Subject(s) - docking (animal) , sorafenib , chemistry , stereochemistry , indole test , binding site , active site , ic50 , hydrophobic effect , cytotoxicity , molecular model , vegf receptors , combinatorial chemistry , biochemistry , enzyme , in vitro , cancer research , biology , medicine , nursing , hepatocellular carcinoma
A series of new indole derivatives 1 – 18 was synthesized and tested for their cytotoxic activity on a panel of 60 tumor cell lines. Additionally, molecular docking was carried out to study their binding pattern and binding affinity in the VEGFR‐2 active site using sorafenib as a reference VEGFR‐2 inhibitor. Based on the molecular docking results, compounds 5a , 5b , 6 , 7 , 14b , 18b , and 18c were selected to be evaluated for their VEGFR‐2 inhibitory activity. Compound 18b exhibited a broad‐spectrum antiproliferative activity on 47 cell lines, with GI % ranging from 31 to 82.5%. Moreover, compound 18b was the most potent VEGFR‐2 inhibitor with an IC 50 value of 0.07 μM, which is more potent than that of sorafenib (0.09 μM). A molecular docking study attributed the promising activity of this series to their hydrophobic interaction with the VEGFR‐2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and/or Asp1046.