“…The substitution pattern and spatial considerations of the p-systems in regard to the quinazoline nucleus proved to be critical for DHFR inhibition. [13][14][15][16][17] In continuation to our previous efforts, [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] a new series of quinazolin-4-one analogs was designed bearing 2-(1,3,4-thiadiazolylor 4-methyl-thiazolyl-)thio-functions as hydrophobic p-system regions replacing the 2-thioalkyl or 2-thioallyl function of the lead compounds D-F; and as isosters of the prototypes G-I to explore the scope and limitations of this new class of DHFR inhibitors. In addition, 6-chloro, 6-methyl, or 6,7-dimethoxy functions, representing electron donating and electron withdrawing substituents; a phenyl or benzyl group at position 3-were introduced to the quinazolin-4-one nucleus in resemblance to the leads D-I.…”