Increasing the binding affinity of VEGFR-2 inhibitors by extending their hydrophobic interaction with the active site: Design, synthesis and biological evaluation of 1-substituted-4-(4-methoxybenzyl)phthalazine derivatives

Wagdy M Eldehna; Sahar M Abou-Seri; Ahmed M El Kerdawy; Rezk R Ayyad; Abdallah M Hamdy; Hazem A Ghabbour; Mamdouh M Ali; Dalal A Abou El Ella

doi:10.1016/j.ejmech.2016.02.029

Increasing the binding affinity of VEGFR-2 inhibitors by extending their hydrophobic interaction with the active site: Design, synthesis and biological evaluation of 1-substituted-4-(4-methoxybenzyl)phthalazine derivatives

Eur J Med Chem. 2016 May 4:113:50-62. doi: 10.1016/j.ejmech.2016.02.029. Epub 2016 Feb 15.

Authors

Wagdy M Eldehna¹, Sahar M Abou-Seri², Ahmed M El Kerdawy³, Rezk R Ayyad⁴, Abdallah M Hamdy⁵, Hazem A Ghabbour⁶, Mamdouh M Ali⁷, Dalal A Abou El Ella⁸

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt. Electronic address: wagdy2000@gmail.com.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt. Electronic address: saharshaarawy_69@yahoo.com.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, Mansoura, Egypt.
⁵ Department of Analytical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
⁷ Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki 12622, Giza, Egypt.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, P.O. Box 11566, Egypt.

PMID: 26922228
DOI: 10.1016/j.ejmech.2016.02.029

Abstract

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 μM). 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 μM). In particular, compounds 7g-i showed IC50 of 0.086, 0.083 and 0.086 μM, respectively, which are better than that of the reference drug sorafenib (IC50 = 0.09 μM).

Keywords: Hydrophobic interaction; Phthalazine; VEGFR-2.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Catalytic Domain / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Hydrophobic and Hydrophilic Interactions
Molecular Structure
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Phthalazines
Protein Kinase Inhibitors
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding