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 0.4–1.0
μM. 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 24.2
μM, 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 π-systems in regard to the quinazoline nucleus proved critical for biological activity.