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Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs
Authors:Al-Rashood Sarah T  Aboldahab Ihsan A  Nagi Mahmoud N  Abouzeid Laila A  Abdel-Aziz Alaa A M  Abdel-Hamide Sami G  Youssef Khairia M  Al-Obaid Abdulrahman M  El-Subbagh Hussein I
Institution:

aDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia

bDepartment of Pharmacology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia

Abstract:In order to produce potent new leads for anticancer drugs, a new series of quinazoline analogs was designed to resemble methotrexate (MTX, 1) structure features and fitted with functional groups believed to enhance inhibition of mammalian DHFR activity. Molecular modeling studies were used to assess the fit of these compounds within the active site of human DHFR. The synthesized compounds were evaluated for their ability to inhibit mammalian DHFR in vitro and for their antitumor activity in a standard in vitro tissue culture assay panel. Compounds 28, 30, and 31 were the most active DHFR inhibitors with IC50 values of 0.5, 0.4, and 0.4 μM, respectively. The most active antitumor agents in this study were compounds 19, 31, 41, and 47 with median growth inhibitory concentrations (GI50) of 20.1, 23.5, 26.7, and 9.1 μM, respectively. Of this series of compounds, only compound 31 combined antitumor potency with potent DHFR inhibition; the other active antitumor compounds (19, 41, and 47) all had DHFR IC50 values above 15 μM, suggesting that they might exert their antitumor potency through some other mode of action. Alternatively, the compounds could differ significantly in uptake or concentration within mammalian cells.
Keywords:4(3H)-Quinazolinone  DHFR inhibitors  Antitumor activity  Molecular modeling studies
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