Non-classical antifolates. Part 2: synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones.

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Al-Omary FA, Abou-Zeid LA, Nagi MN, Habib el-SE, Abdel-Aziz AA, El-Azab AS, Abdel-Hamide SG, Al-Omar MA, Al-Obaid AM, El-Subbagh HI

Non-classical antifolates. Part 2: synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones.

Bioorg Med Chem. 2010 Apr 15;18(8):2849-63. doi: 10.1016/j.bmc.2010.03.019. Epub 2010 Mar 12.

PubMed ID

20350811 [ View in PubMed

]

Abstract

A new series of 2,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 22, 33-37, 39-43, and 45 proved to be active DHFR inhibitors with IC(50) range of 0.4-1.0microM. Compound 18 showed broad-spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compounds 34 and 36 showed antitumor activity at GI(50) (MG-MID) concentrations of 11.2, and 24.2microM, respectively. Molecular modeling study including flexible alignment; electrostatic, hydrophobic mappings; and pharmacophore prediction were performed. A main featured pharmacophore model was developed which justifies the importance of the main pharmacophoric groups as well as of their relative distances. The substitution pattern and spatial considerations of the pi-systems in regard to the quinazoline nucleus proved critical for biological activity.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Gentamicin	Dihydrofolate reductase	Protein	Humans	Unknown	Not Available	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Methotrexate	Dihydrofolate reductase	IC 50 (nM)	80	N/A	N/A	Details