Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 113, Issue -, Pages 50-62Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.02.029
Keywords
Phthalazine; VEGFR-2; Hydrophobic interaction
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Funding
- Deanship of Scientific Research at King Saud University [RGP-1436-038]
- National Institutes of Health National Center for Research Resources [2P41RR001081]
- National Institute of General Medical Sciences [9P41GM103311]
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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A series of anilinophthalazine derivatives 4a-j was initially synthesized and tested for its VEGFR-2 inhibitory activity where it showed promising activity (IC50 = 0.636-5.76 mu M). Molecular docking studies guidance was used to improve the binding affinity for series 4a-j towards VEGFR-2 active site. This improvement was achieved by increasing the hydrophobic interaction with the hydrophobic back pocket of the VEGFR-2 active site lined with the hydrophobic side chains of Ile888, Leu889, Ile892, Val898, Val899, Leu1019 and Ile1044. Increasing the hydrophobic interaction was accomplished by extending the anilinophthalazine scaffold with a substituted phenyl moiety through an uriedo linker which should give this extension the flexibility required to accommodate itself deeply into the hydrophobic back pocket. As planned, the designed uriedo-anilinophthalazines 7a-i showed superior binding affinity than their anilinophthalazine parents (IC50 = 0.083-0.473 mu M). In particular, compounds 7g-i showed IC50 of 0.086, 0.083 and 0.086 mu M, respectively, which are better than that of the reference drug sorafenib (IC50 = 0.09 mu M). (C) 2016 Elsevier Masson SAS. All rights reserved.
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