الفهرس 
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Abstract
Quinazoline derivatives are an important class of heterocyclic compounds, many of them possessed a wide range of biological activities such as anticancer, analgesic, antifungal, antibacterial, anti-inflammatory and anticonvulsant activities. Considering the biological significance of quinazoline nucleus, we aimed to design and synthesize new derivatives and screen them for their cytotoxic activity via inhibition of epithelial growth factor receptor (EGFR) kinase enzyme to prove the work rationale.
This thesis consists of the following parts:
1. Introduction:
In this section, an overview on cancer and anticancer agents was discussed. Moreover, it included a literature review of protein kinases such as EGFR. Finally, the various biological and pharmacological activities of quinazolines with a focus on their anticancer activities were discussed.
2. Aim of the work:
It included the rationale upon which the newly synthesized compounds were designed.
3. Discussion:
This part dealt with the discussion of the various experimental methods and conditions of reactions, especially those used for the synthesis of the prepared compounds and the elucidation of their structures through infrared, mass, elemental analyses, 1H-NMR and 13C-NMR spectra.
4. Experimental:
It represented the practical procedures used for the synthesis of reported and new intermediates, as well as new final compounds. Also, it included their physical, microanalytical and spectral data. In order to obtain the new compounds, the following compounds were prepared:
Reported intermediates (6 compounds):
• 2-Methylquinazolin-4(3H)-one II.
• (E)-2-(4-Methoxystyryl)quinazolin-4(3H)-one III.
• (E)-4-Chloro-2-(4-methoxystyryl)quinazoline IV.
• 4-Chloro-2-methylquinazoline VII.
• 2-(Bromomethyl)quinazolin-4(3H)-one XVIII.
• 2-(Hydrazinylmethyl)quinazolin-4(3H)-one XIX.
New intermediates (5 compounds):
• N-(4-Chlorophenyl)-2-methylquinazolin-4-amine VIII.
• N-(5-Methylisoxazol-3-yl)-4-((2-methylquinazolin-4-yl)amino)benzenesulfonamide X.
• N1-(2-Methyl quinazolin-4-yl)benzene-1,4-diamine XII.
• N1-(2-Methylquinazolin-4-yl)benzene-1,3-diamine XIV.
• (E)-4-Chloro-2-((2-(4-nitrobenzylidene)hydrazinyl)methyl)quinazoline XXI.
New final compounds ( 34 compounds):
• (E)-4-((2-(4-Methoxystyryl)quinazolin-4-yl)amino)phenol Va.
• (E)-N-(4-Chlorophenyl)-2-(4-methoxystyryl)quinazolin-4-amine Vb.
• (E)-2-(4-Methoxystyryl)-N-(4-nitrophenyl)quinazolin-4-amine Vc.
• (E)-Ethyl 4-((2-(4-methoxystyryl)quinazolin-4-yl)amino)benzoate Vd.
• (E)-N-(4-((2-(4-Methoxystyryl)quinazolin-4-yl)amino)phenyl)acetamide Ve.
• (E)-N-((4-((2-(4-Methoxystyryl)quinazolin-4-yl)amino)phenyl)sulfonyl)acetamide VIa.
• (E)-N-Carbamimidoyl-4-((2-(4-methoxystyryl)quinazolin-4-yl)amino)benzenesulfonamide VIb.
• (E)-4-((2-(4-Methoxystyryl)quinazolin-4-yl)amino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide VIc.
• (E)-4-((2-(4-Methoxystyryl)quinazolin-4-yl)amino)-N-(pyrimidin-2-yl)benzenesulfonamide VId.
• (E)-N-(4,6-Dimethylpyrimidin-2-yl)-4-((2-(4-methoxystyryl)quinazolin-4-yl)amino)benzenesulfonamide VIe.
• (E)-4-(2-(4-((4-Chlorophenyl)amino)quinazolin-2-yl)vinyl)phenol IXa.
• (E)-N-(4-Chlorophenyl)-2-(4-chlorostyryl)quinazolin-4-amine IXb.
• (E)-N-(4-Chlorophenyl)-2-(4-nitrostyryl)quinazolin-4-amine IXc.
• (E)-N-(4-Chlorophenyl)-2-(4-(dimethylamino)styryl)quinazolin-4-amine IXd.
• (E)-4-(2-(4-((4-Chlorophenyl)amino)quinazolin-2-yl)vinyl)-2-methoxyphenol IXe.
• (E)-4-((2-(4-Hydroxystyryl)quinazolin-4-yl)amino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide XIa.
• (E)-4-((2-(4-Chlorostyryl)quinazolin-4-yl)amino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide XIb.
• (E)-N-(5-Methylisoxazol-3-yl)-4-((2-(4-nitrostyryl)quinazolin-4-yl)amino)benzenesulfonamide XIc.
• (E)-4-((2-(4-Hydroxy-3-methoxystyryl)quinazolin-4-yl)amino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide XId.
• 1-(4-((2-Methylquinazolin-4-yl)amino)phenyl)-3-phenylurea XIIIa.
• 1-(4-((2-Methylquinazolin-4-yl)amino)phenyl)-3-phenylthiourea XIIIb.
• 1-(4-Chlorophenyl)-3-(4-((2-methylquinazolin-4-yl)amino)phenyl)urea XIIIc.
• 1-(3-((2-Methylquinazolin-4-yl)oxy)phenyl)-3-phenylurea XVa.
• 1-(3-((2-Methylquinazolin-4-yl)oxy)phenyl)-3-phenylthiourea XVb.
• 1-(4-Chlorophenyl)-3-(3-((2-methylquinazolin-4-yl)oxy)phenyl)urea XVc.
• (E)-1-(4-Chlorophenyl)-3-(3-((2-(4-methoxystyryl)quinazolin-4-yl)amino)phenyl)urea XVI.
• (E)-N1-(2-(4-Methoxystyryl)quinazolin-4-yl)benzene-1,4-diamine XVII.
• (E)-2-((2-(4-Hydroxybenzylidene)hydrazinyl)methyl)quinazolin-4(3H)-one XXa.
• (E)-2-((2-(4-Chlorobenzylidene)hydrazinyl)methyl)quinazolin-4(3H)-one XXb.
• (E)-2-((2-(4-Methoxybenzylidene)hydrazinyl)methyl)quinazolin-4(3H)-one XXc.
• (E)-2-((2-(4-Nitrobenzylidene)hydrazinyl)methyl)quinazolin-4(3H)-one XXd.
• (E)-N-(4-Chlorophenyl)-2-((2-(4-nitrobenzylidene)hydrazinyl)methyl)quinazolin-4-amine XXII.
• (E)-N-(5-Methylisoxazol-3-yl)-4-((2-((2-(4-nitrobenzylidene)hydrazinyl)methyl)quinazolin-4-yl)amino)benzenesulfonamide XXIII.
• 2-(((3-Chloro-2-(4-nitrophenyl)-4-oxoazetidin-1-yl)amino)methyl)quinazolin-4(3H)-one XXIV.
5. Antitumor Screening
Thirty nine compounds were chosen by U. S. National Cancer Institute for antitumor screening. The results revealed that all tested compounds showed moderate activity against panels of cell lines especially non-small lung cancer and breast cancer.
Cytotoxicity study and EGFR enzyme assay
Only the most active ten compounds were selected for IC50 determination in lung cancer A549 by MTT assay and EGFR inhibition assay determination using Lapatinib as a reference drug at the confirmatory diagnostic unit at Vacsera, Cairo, EGYPT.
EGFR assay in A549 cell line
A549 cell line was firstly treated with each target compounds then lysed for determination of percent of drug inhibition for EGFR enzyme in this cell line.
Cell cycle analysis and apoptosis assay
Cell cycle analysis was carried out and the results revealed that compounds VIc and XXd processed cell arrest at G2/M phase and apoptosis phase. Accordingly, apoptosis assay by Annexin-V assay was carried out and confirmed ability of target compounds to induce apoptosis.
Effect of tested compounds on level of active Caspase-3
Compounds VIc and XXd were tested for their Caspase-3 activation to confirm their apoptosis induction activity at confirmatory diagnostic unit at Vacsera.
Molecular Docking
Most active compounds were docked into EGFR active site (PDB: 1XXK) and compared with the reference lapatinib to determine their possible binding mode and energies affinity.
6. References:
This part consist of 132 references between 1895 and 2020.