Quinazolinone-Amino Acid Hybrids as Dual Inhibitors of EGFR Kinase and Tubulin Polymerization

Mohamed F Zayed; Heba S Rateb; Sahar Ahmed; Osama A Khaled; Sabrin R M Ibrahim

doi:10.3390/molecules23071699

Quinazolinone-Amino Acid Hybrids as Dual Inhibitors of EGFR Kinase and Tubulin Polymerization

Molecules. 2018 Jul 12;23(7):1699. doi: 10.3390/molecules23071699.

Authors

Mohamed F Zayed^{1

2}, Heba S Rateb^{3

4}, Sahar Ahmed^{5

6}, Osama A Khaled^{7

8}, Sabrin R M Ibrahim^{9

10}

Affiliations

¹ Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah 41477, Al-Munawarah, Saudi Arabia. [email protected].
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt. [email protected].
³ Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah 41477, Al-Munawarah, Saudi Arabia. [email protected].
⁴ Department of Pharmaceutical and Medicinal Chemistry, Pharmacy College, Misr University for Science and Technology, Cairo 12568, Egypt. [email protected].
⁵ Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah 41477, Al-Munawarah, Saudi Arabia. [email protected].
⁶ Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assuit 71526, Egypt. [email protected].
⁷ Department of Physical Therapy, College of Medical Rehabilitation Sciences, Taibah University, Al-Madinah 41477, Al-Munawarah, Saudi Arabia. [email protected].
⁸ Department of Basic Science, Faculty of Physical Therapy, Cairo University, Cairo 12613, Egypt. [email protected].
⁹ Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah 41477, Al-Munawarah, Saudi Arabia. [email protected].
¹⁰ Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. [email protected].

Abstract

Some fluoroquinazolinones (A⁻H) were designed, synthesized and biologically evaluated for their antitumor activity against the two cell lines, MCF-7 and MDA-MBA-231. New derivative G (IC₅₀ = 0.44 ± 0.01 µM) showed antitumor activity, better than that of the reference drug erlotinib (IC₅₀ = 1.14 ± 0.04 µM) against MCF-7. New derivative E (IC₅₀ = 0.43 ± 0.02 µM) showed higher activity than the reference drug erlotinib (IC₅₀ = 2.55 ± 0.19 µM) against MDA-MBA-231. Furthermore, the EGFR (epidermal growth factor receptor) and tubulin inhibition assays were carried out for the highest active derivatives to reveal the expected mechanism of action. They exhibited significant results compared to the reference drugs. Molecular docking simulations were performed on EGFR and tubulin binding sites to rationalize the experimental results and describe their binding modes. The results of the molecular modeling study were correlated with that of the antitumor screening.

Keywords: EGFR inhibitor; antitumor; fluoroquinazolinones; synthesis; tubulin inhibitor.

MeSH terms

ErbB Receptors* / antagonists & inhibitors
ErbB Receptors* / chemistry
ErbB Receptors* / metabolism
Humans
MCF-7 Cells
Molecular Docking Simulation*
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Quinazolines* / chemical synthesis
Quinazolines* / chemistry
Quinazolines* / pharmacology
Tubulin Modulators* / chemical synthesis
Tubulin Modulators* / chemistry
Tubulin Modulators* / pharmacology
Tubulin* / chemistry
Tubulin* / metabolism

Substances

Protein Kinase Inhibitors
Quinazolines
Tubulin
Tubulin Modulators
EGFR protein, human
ErbB Receptors