Nonclassical antifolates, part 5. Benzodiazepine analogs as a new class of DHFR inhibitors: Synthesis, antitumor testing and molecular modeling study

A new series of tetrahydro-quinazoline and tetrahydro-1H-dibenzo[b,e][1,4]diazepine analogs were synthesized and tested for their DHFR inhibition and in vitro antitumor activity. Compound 35 showed a remarkable DHFR inhibitory potency (IC50, 0.004 mM) which is twenty fold more active than metho- trexate (MTX). Compounds 17 and 23 proved to be fifteen fold more active than the known antitumor 5- FU, with MG-MID GI50, TGI, and LC50 values of 1.5, 46.8, 93.3 and 1.4, 17.4, 93.3 mM, respectively. Com- puter modeling studies allowed the identification that methoxy and methyl substituents, the p-system of the chalcone core, the nitrogen atoms, on the dibenzodiazepine ring as pharmacophoric features essential for activity. These mark points could be used as template model for further future optimization

Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study

A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC 0.03 mM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors