STRUCTURE-BASED DESIGN AND SYNTHESIS OF LIPOPHILIC 2,4-DIAMINO-6-SUBSTITUTED QUINAZOLINES AND THEIR EVALUATION AS INHIBITORS OF DIHYDROFOLATE REDUCTASES AND POTENTIAL ANTITUMOR AGENTS

The synthesis and biological activities of 14 6-substituted 2,4-diamin oquinazolines are reported. These compounds were designed to improve t he cell penetration of a previously reported series of 2,4-diamino-6-s ubstituted-pyrido[2,3-d]pyrimidines which had shown significant potenc y and remarkable selectivity for Toxoplasma gondii dihydrofolate reduc tase (DHFR), but had much lower inhibitory effects on the growth of T. gondii cells in culture. The target N9-H analogues were obtained via r egiospecific reductive amination of the appropriate benzaldehydes with 2,4,6-triaminoquinazoline, which, in turn, was synthesized from 2,4-d iamino-6-nitroquinazoline. The N9-CH3 analogues were synthesized via a regiospecific reductive methylation of the corresponding N9-H precurs ors. The compounds were evaluated as inhibitors of DHFR from human, Pn eumocystis carinii, T. gondii, rat liver, Lactobacillus casei, and Esc herichia coli, and selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. These analogues displayed potent T. gondii DHFR inhibition as well as inhibition of the growth of T. g ondii cells in culture. Further, selected analogues were potent inhibi tors of the growth of tumor cells in culture in the in vitro screening program of the National Cancer institute with GI(50)s in the nanomola r and subnanomolar range. Crystallographic data for the ternary comple x of hDHFR-NADPH and oxybenzyl)-N-methylamino]-pyrido[2,3-d]pyrimidine , 1c, reveal the first structural details for a reversed N9-C10 folate bridge geometry as well as the first conformational details of a hybr id piritrexim-trimetrexate analogue.