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

Abstract

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)methy l] quinazoline (10) had an IC50 of 0.012 microM 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 microM 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 microM) 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-[N-(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.

Identification of Cryptosporidium parvum Dihydrofolate Reductase Inhibitors by Complementation in Saccharomyces cerevisiae

“…These lipophilic DHFR inhibitors are assumed to cross the plasma membrane by passive or facilitated diffusion and, therefore, to obviate drug susceptibility and resistance problems associated with carrier-or receptor-mediated folate transport mechanisms (7). Many of these compounds have previously been assayed against P. carinii DHFR and T. gondii DHFR-TS in vitro (48,49,(51)(52)(53)(54)(55)(56). For example, the IC 50 of PY875 against the P. carinii DHFR enzyme in vitro was ϳ7 M (51), suggesting that PY875 might also inhibit the growth of Pc-yeast; Table 6 shows this to indeed be the case.…”

“…The activities of many of these drugs against these parasites or their purified DHFR enzymes was known already. For example, members of the PY series had been tested in vitro to measure inhibition of the P. carinii or T. gondii enzyme (48,49,(52)(53)(54)56). We knew at the outset which compounds were effective in vitro against the DHFRs of other pathogens, which allowed us to quickly identify drugs that did not effectively penetrate the yeast host.…”

Preclinical Evaluation of the Antifolate QN254, 5-Chloro-N′6′-(2,5-Dimethoxy-Benzyl)-Quinazoline-2,4,6-Triamine, as an Antimalarial Drug Candidate

“…Standard drugs for in vivo efficacy testing were obtained from Mepha, Ltd., Switzerland (artesunate); Sigma (United States) (chloroquine diphosphate); and F. Hoffmann-LaRoche, Ltd., Switzerland (mefloquine hydrochloride). QN254 was prepared as described elsewhere (39).…”

Cobalt(II) Chloride Catalyzed one Pot Synthesis of 2-substituted and 3-substituted-4(3H)- Quinazolinones

“…Furthermore, 4(3H)-quinazolinones substituted at 2,3-position derivatives play a pivotal role in the hypertensive activity. 9,10 ORIENTAL JOURNAL OF CHEMISTRY www.orientjchem.org Several bioactive natural products such as febrifugine and isofebrifugine contain quinazolinone moieties with potential anti-malarial activity 11 Similarly quinazolinone containing moieties have been known as tyrosine kinase inhibitors, 12 dihydrofolate reductase inhibitors, 13 and tubulin polymerization inhibitors.…”