6-Aryl and Heterocycle Quinazoline Derivatives as Potent EGFR Inhibitors with Improved Activity toward Gefitinib-Sensitive and -Resistant Tumor Cell Lines

Authors

  • Mostafa M. Hamed,

    1. Pharmaceutical and Medicinal Chemistry, Saarland University, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, 66123 Saarbrücken (Germany)
    2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835 (Egypt)
    Search for more papers by this author
  • Prof. Dr. Dalal A. Abou El Ella,

    1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University (Egypt)
    2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University (Saudi Arabia)
    Search for more papers by this author
  • Dr. Adam B. Keeton,

    1. Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Suite 3029, Mobile, AL 36604 (USA)
    Search for more papers by this author
  • Prof. Dr. Gary A. Piazza,

    1. Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Suite 3029, Mobile, AL 36604 (USA)
    Search for more papers by this author
  • Prof. Dr. Ashraf H. Abadi,

    1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835 (Egypt)
    Search for more papers by this author
  • Prof. Dr. Rolf W. Hartmann,

    1. Pharmaceutical and Medicinal Chemistry, Saarland University, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, 66123 Saarbrücken (Germany)
    Search for more papers by this author
  • Dr. Matthias Engel

    Corresponding author
    1. Pharmaceutical and Medicinal Chemistry, Saarland University, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, 66123 Saarbrücken (Germany)
    • Pharmaceutical and Medicinal Chemistry, Saarland University, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, 66123 Saarbrücken (Germany)

    Search for more papers by this author

Abstract

A group of novel anilinoquinazoline derivatives with variable aryl and heterocyclic substituents at position 6 were synthesized and tested for their EGFR-inhibitory activity. Aryl and heterocyclic rings were attached to the quinazoline scaffold through different linkages such as imine, amide, and thiourea. Most of the aryl and heterocyclic derivatives showed potent inhibition of wild-type EGFR with IC50 values in the low nanomolar range. Among these, thiourea derivatives 6 a, 6 b and compound 10 b also retained significant activity toward the gefitinib-insensitive EGFRT790M/L858R mutant, displaying up to 24-fold greater potency than gefitinib. In addition, cell growth inhibitory activity was tested against cancer cell lines with wild-type (KB cells) and mutant EGFR (H1975 cells). Several compounds including 6 a were found to be more potent than the reference compound gefitinib toward both cell lines, as was the case for compound 10 b against H1975 cells. Therefore, compounds 6 a and 10 b in particular may serve as new leads for the development of inhibitors effective against wild-type EGFR as well as gefitinib-resistant mutants.

Ancillary