10.1021/jm980081y.s001 Aleem Gangjee Aleem Gangjee Anup P. Vidwans Anup P. Vidwans Anil Vasudevan Anil Vasudevan Sherry F. Queener Sherry F. Queener Roy L. Kisliuk Roy L. Kisliuk Vivian Cody Vivian Cody Ruming Li Ruming Li Nikolai Galitsky Nikolai Galitsky Joe R. Luft Joe R. Luft Walter Pangborn Walter Pangborn 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 American Chemical Society 1998 analogue Toxoplasma gondii dihydrofolate reductase gondii cells GI culture National Cancer Institute tumor cells diamino regiospecific reductive amination Potential Antitumor Agents regiospecific reductive methylation inhibitor gondii DHFR inhibition 1998-08-12 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/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/3683661 The synthesis and biological activities of 14 6-substituted 2,4-diaminoquinazolines are reported. These compounds were designed to improve the cell penetration of a previously reported series of 2,4-diamino-6-substituted-pyrido[2,3-<i>d</i>]pyrimidines which had shown significant potency and remarkable selectivity for <i>Toxoplasma gondii</i> dihydrofolate reductase (DHFR), but had much lower inhibitory effects on the growth of <i>T</i>. <i>gondii</i> cells in culture. The target N9−H analogues were obtained via regiospecific reductive amination of the appropriate benzaldehydes with 2,4,6-triaminoquinazoline, which, in turn, was synthesized from 2,4-diamino-6-nitroquinazoline. The N9−CH<sub>3</sub> analogues were synthesized via a regiospecific reductive methylation of the corresponding N9−H precursors. The compounds were evaluated as inhibitors of DHFR from human, <i>Pneumocystis carinii</i>, <i>T</i>. <i>gondii</i>, rat liver, <i>Lactobacillus</i> <i>casei</i>, and <i>Escherichia</i> <i>coli</i>, and selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. These analogues displayed potent <i>T</i>. <i>gondii</i> DHFR inhibition as well as inhibition of the growth of <i>T</i>. <i>gondii</i> cells in culture. Further, selected analogues were potent inhibitors of the growth of tumor cells in culture in the in vitro screening program of the National Cancer Institute with GI<sub>50</sub>s in the nanomolar and subnanomolar range. Crystallographic data for the ternary complex of hDHFR−NADPH and 2,4-diamino-6-[<i>N</i>-(2‘,5‘-dimethoxybenzyl)-<i>N</i>-methylamino]pyrido[2,3-<i>d</i>]pyrimidine, <b>1c</b>, reveal the first structural details for a reversed N9−C10 folate bridge geometry as well as the first conformational details of a hybrid piritrexim−trimetrexate analogue.