N9-Substituted 2,4-Diaminoquinazolines: Synthesis and Biological Evaluation of Lipophilic Inhibitors of Pneumocystis carinii and Toxoplasma gondii Dihydrofolate Reductase

Abstract

N9-substituted 2,4-diaminoquinazolines were synthesized and evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). Reduction of commercially available 2,4-diamino-6-nitroquinazoline 14 with Raney nickel afforded 2,4,6-triaminoquinazoline 15. Reductive amination of 15 with the appropriate benzaldehydes or naphthaldehydes, followed by N9-alkylation, afforded the target compounds 5–13. In the 2,5-dimethoxybenzylamino substituted quinazoline analogues, replacement of the N9—CH3 group of 4 with the N9—C2H5 group of 8 resulted in a 9- and 8-fold increase in potency against pcDHFR and tgDHFR, respectively. The N9—C2H5 substituted compound 8 was highly potent, with IC50 values of 9.9 and 3.7 nM against pcDHFR and tgDHFR, respectively. N9-propyl and N9-cyclopropyl methyl substitutions did not afford further increases in potency. This study indicates that the N9-ethyl substitution is optimum for inhibitory activity against pcDHFR and tgDHFR for the 2,4-diaminoquinazolines. Selectivity was unaffected by N9 substitution.

Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs

“…The 2,4‐diaminoquinazoline and diaminopyrroloquinazoline scaffolds are well known for their high potency on bacterial DHFR variants and have been extensively studied as part of several optimization programs . Most of these efforts have focused on 6‐substituted derivatives.…”

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

“…Most of these screens were focused on developing inhibitors against known essential enzymes, such as DHFR, DHPS, and nucleoside triphosphate hydrolase (NTPase). However, due to the toxicity of clinically available antifolate drugs, many of the initial screens were focused on identifying additional compounds that specifically inhibited T. gondii DHFR (33,34,(106)(107)(108)(109)(110)(111) and DHPS (39,112) while avoiding host effects. Most of these small-scale screens were performed to identify compounds that were active against these enzymes, but very few of these studies report T. gondii in vivo data (37,113,114).…”

Recent advances in the chemistry and biology of pyridopyrimidines

“…One target to treat infection with these organisms is the inhibition of the dihydrofolate reductase (DHFR) enzyme which converts dihydrofolate into tetrahydrofolate, a cofactor required for the synthesis of purines. DHFR has been successfully targeted in antimicrobial therapy [14,55,56].…”