الفهرس 
Study of Substituents Effect on the Antitumor Activity of Certain Quinazolinones: Synthesis and Biological Evaluation
ContentsOnly 14 pages are availabe for public view
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Abstract
New 2-mercapto-quinazolin-4-one analogues were synthesized and tested for their in vitro anticancer activity, dihydrofolate reductase (DHFR) inhibition and epidermal growth factor tyrosine kinase (EGFR-TK) inhibition activities.
Compound 112showed 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 binging pocket like MTX. Compound 112 is nearly the same binding mode as gefitinib as it interacted with Lys A745 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.