Study of substituents effect on the antitumor activity of certain quinazolinones: synthesis and biological evaluation / By Yomna Ibrahim Hassan El-Gazzar, (Assistant Lecturer of Pharmaceutical Chemistry, Faculty of pharmacy, Future University in Egypt); Supervision of Prof. Dr. Riham François George (Professor of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Prof. Dr.Dr. Hussein Ibrahim El-Subbagh, Professor of Pharmaceutical Chemistry, Faculty of Pharmacy, Mansura University, Prof. Dr. Khairia Mohamed Youssef, Professor of pharmaceutical Organic Chemistry, Faculty of pharmacy, Future University in Egypt, Prof. Dr. Hanan Hanna Georgey, Professor of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University).

Supervision of Prof. Dr. Riham François George (Professor of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Prof. Dr.Dr. Hussein Ibrahim El-Subbagh, Professor of Pharmaceutical Chemistry, Faculty of Pharmacy, Mansura University, Prof. Dr. Khairia Mohamed Youssef, Professor of pharmaceutical Organic Chemistry, Faculty of pharmacy, Future University in Egypt, Prof. Dr. Hanan Hanna Georgey, Professor of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University).

Thesis (P.hD.)-Cairo University, Faculty of pharmacy, Department of Pharmaceutical Chemistry, 2022.

Includes bibliographical references.

Quinazoline derivatives assign an important class of heterocyclic compounds that possessed a wide range of biological activities such as anti-inflammatory, antifungal, antibacterial, anticancer, and anticonvulsant activities. The presence of natural bioactive products of quinazolines inspires researchers to take the quinazoline nucleus as a core for the synthesis of a multitude of derivatives. The epidermal growth factor receptor (EGFR) is a tyrosine kinase that is over-expressed in a significant number of human tumors (e.g., colon, ovarian, breast, and prostate), so EGFR was recognized as a significant target for the management of cancer diseases. Dihydrofolate reductase (DHFR) is an enzyme that catalyzes the reduction of folic acid or dihydrofolic acid into tetrahydrofolic acid, which is then converted into N5, N10-methylenetetrahydrofolate. This later compound functions as the source of the methyl group to convert dUMP into dTMP. So, inhibition of DHFR has been an attractive goal for the development of agents against bacterial and parasitic infections as well as cancer. Therefore, we aimed to design and synthesize new quinazoline derivatives and screen them for their anti-cancer activity. Moreover, evaluated for their EGFR-TK inhibition and in vitro DHFR activities. On the light of these findings, a new series of 2-mercapto-quinazolin-4-one analogues was prepared. Compound 112 showed a broad-spectrum anticancer activity with high safety profile and selectivity index. It showed GI50, TGI, and LC50 (MG-MID) values of 15.1, 52.5, and 91.2 μM, respectively using 5-Fluorouracil (5-FU) as a positive control, also it showed EGFR-TK inhibitory activity with IC50 13.40 nM compared to gefitinib (IC50 18.14 nM) and DHFR inhibitory potency with 0.30 M compared to methotrexate (MTX, IC50 0.08 M). Similarly, it encouraged cell cycle arrest and apoptosis on colo 205 colon cancer cells. Compound 128 showed a remarkable DHFR inhibitory potency with IC50 of 0.03 M which is more active than methotrexate (IC50 of 0.08 M). Moreover, compounds 109 and 145 showed DHFR inhibition comparable to MTX. However, compounds 104, 125, 142, and 147 showed moderate DHFR inhibitor activity with IC50 = 0.16, 0.12, 0.16, and 0.14 M, respectively. In a molecular modeling study, compound 128 showed high-affinity binding towards the amino acid residues Lys68, Asn64, and Phe34 by hydrogen bonding acceptor, hydrogen bonding acceptor, and arene-arene interaction, respectively within DHFR binding pocket like MTX. Compound 112 is nearly the same binding mode as gefitinib as it interacted with LysA745 amino acid via π-π interaction. The obtained model and pattern of substitution could be used for the further development of DHFR and EGFR-TK inhibitors.

Text in English, abstracts in English and Arabic.