2,4-Diamino-5-chloroquinazoline Analogs of Trimetrexate and Piritrexim: Synthesis and Antifolate Activity

Andre Rosowsky, Clara E. Mota, Joel E. Wright, Sherry F. Queener

Research output: Contribution to journalArticle

44 Scopus citations


Ten heretofore undescribed 2,4-diamino-5-chloroquinazoline analogues of trimetrexate (TMQ) and piritrexim (PTX) were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) from rat liver, Pneumocystis carinii, and Toxoplasma gondii. The most active quinazolines against both the P. carinii and the T. gondii enzyme were those with an ArCH2-NH or ArNHCH2 side chain. Among ArNH(CH2)n compounds with n = 1-3 and either 2′,5′-dimethoxyphenyl or 3′,4′,5′-trimethoxyphenyl as the Ar moiety, activity decreased in the order n = 1 > n = 2 > n = 3. The best inhibitor of P. carinii DHFR, 2,4-diamino-5-chloro-6-[(N-methyl-3′,4′,5′-trimethoxyanilino) methyl]quinazoline (10) had an IC50 of 0.012 μM and was slightly more potent than TMQ and PTX. Compound 10 was also the best inhibitor of T. gondii DHFR, with an IC50 of 0.0064 μM. corresponding again to a minor increase in activity over TMQ and PTX. However, as with these standard agents, 10 showed no appreciable selectivity for either the P. carinii or T. gondii enzyme relative to the rat liver enzyme. The highest selectivity achieved in this limited series was with 2,4-diamino-5-chloro-6-[N-(3′,4′,5′-trimethoxybenzyl)-N- methylamino]quinazoline (17) against T. gondii DHFR. While 17 (IC50 = 0.016 μM) was somewhat less potent than 10, its selectivity, as defined by the ratio IC50(rat liver )/IC50(T. gondii) was ca. 30-fold higher than that of TMQ or PTX. Two compounds, 2,4-diamino-5-chloro-6-[(3′,4′,5′-trimethoxyanilino)methyl] quinazoline (9) and 2,4-diamino-5-chloro-6-[Ar-(3′,4′,5′-trimethoxybenzyl)amino] quinazoline (15), were also tested against human DHFR and were found to have an IC50/[E] of 0.5, indicating that their binding was near-stoichiometric.

Original languageEnglish (US)
Pages (from-to)4522-4528
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number26
StatePublished - Dec 1 1994

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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