2. Academic Validation
  3. Discovery of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors: Design, synthesis, and anti-proliferative evaluation

Discovery of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors: Design, synthesis, and anti-proliferative evaluation

  • Bioorg Chem. 2020 Dec;105:104380. doi: 10.1016/j.bioorg.2020.104380.
Ibrahim H Eissa 1,  Abdel-Ghany A El-Helby 2,  Hazem A Mahdy 2,  Mohamed M Khalifa 2,  Hamdy A Elnagar 2,  Ahmed B M Mehany 3,  Ahmed M Metwaly 4,  Mostafa A Elhendawy 5,  Mohamed M Radwan 6,  Mahmoud A ElSohly 7,  Khaled El-Adl 8
Affiliations

Affiliations

  • 1 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: [email protected].
  • 2 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
  • 3 Zoology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt.
  • 4 Pharmacognosy Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
  • 5 Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt; National Center for Natural Products Research, University of Mississippi, MS 38677, USA.
  • 6 National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
  • 7 National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA.
  • 8 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt. Electronic address: [email protected].
PMID: 33128967 DOI: 10.1016/j.bioorg.2020.104380
Abstract

Sixteen novel quinazoline-based derivatives were designed and synthesized via modification of the VEGFR-2 reported inhibitor 7 in order to increase the binding affinity of the designed compounds to the receptor active site. The designed compounds were evaluated for their VEGFR-2 inhibitory effects. Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of Cancer. The bioactivity of the new compounds was performed against HepG-2, MCF-7 and HCT-116 cell lines. Doxorubicin and sorafenib were used as positive controls. Compound 18d was observed to have promising cytotoxic activity (IC50 = 3.74 ± 0.14, 5.00 ± 0.20 and 6.77 ± 0.27 µM) in comparison to the reference drug doxorubicin (IC50 = 8.28, 9.63 and 7.67 µM) and sorafenib (IC50 = 7.31, 9.40 and 7.21 µM). The most active compounds were tested for their in vitro VEGFR-2 inhibitory activities. Results of VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Thus, compound 18d showed VEGFR-2 inhibitory activity (IC50 = 0.340 ± 0.04 µM) superior to that of the reference drug, sorafenib (IC50 = 0.588 ± 0.06 µM). Furthermore, docking study was performed in order to understand the binding pattern of the new compounds into VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key Amino acids in the active site, Glu883 and Asp1044, as well as their hydrophobic interaction with the receptor hydrophobic pocket. Results of cytotoxic activities, in vitro VEGFR-2 inhibition together with docking study argument the advantages of the synthesized analogues as promising anti-angiogenic agents.

Keywords

Antiangiogenesis; Antiproliferative; Docking studies; Quinazolin-4(3H)-one; VEGFR-2.

Figures
Products