“…A similar methodology, involving base-catalyzed cyclization of 2,6-diamino-4-hydroxypyrimidine and nitromalonaldehyde, has been reported by Price et al. for the synthesis of the 2-amino-4-hydroxy-6-nitropyrido[2,3- d ]pyrimidine. 1 …”
Fifteen novel nonclassical and two classical 2,4-diamino-6-(benzylamino)pyrido[2,3-d]pyrimidine antifolates were synthesized as potential inhibitors of Pneumocystis carinii, (pc) Toxoplasma gondii, (tg) rat liver (rl), and human (h) recombinant dihydrofolate reductases (DHFR). These analogues lack a 5-methyl substitution which has been shown to be important for increased hDHFR inhibitory activity. In addition, they contain a reversal of the C9-N10 bridge present in folates and most antifolates. The synthesis of the compounds involved the reaction of 2,4,6-triaminopyrimidine with the sodium salt of nitromalonaldehyde to afford the key intermediate 2,4-diamino-6-nitropyrido[2,3-d]pyrimidine (7), in a single step. Reduction of 7 to the 2,4,6-triaminopyrido[2,3-d]pyrimidine (8), followed by reductive amination with the appropriate benzaldehydes or phenylacetaldehydes afforded the target compounds. N9 methylation of these analogues was carried out using formaldehyde and sodium cyanoborohydride. The analogues demonstrated significant inhibition of pcDHFR and tgDHFR. N9 methylation significantly increased DHFR inhibitory potency. Compound 11, the 3'4'5'-trimethoxy-substituted analogue with a selectivity ratio of 9.4 for tgDHFR (compared to rlDHFR) was the most selective analogue of the nonclassical series. Compound 22, the N9 methyl 2'5'-dimethoxy-substituted analogue was the most potent analogue against tgDHFR (IC 50 = 6.3 nM) and was the second most selective analogue for tgDHFR (compared to rlDHFR) in the nonclassical series. The naphthyl-substituted analogues 23-25 were generally more potent against rlDHFR than against pcDHFR and tgDHFR. Selected analogues were also evaluated against Streptococcus faecium (sf) DHFR, Escherichia coli (ec) DHFR, Lactobacillus casei (lc) DHFR and tgDHFR with hDHFR as the mammalian reference, under slightly different assay conditions than those employed for rlDHFR. Analogues 11 and 22 had selectivity ratios of greater than 100 for tgDHFR (compared to hDHFR). Analogue 22 in particular, was the most selective analogue of the nonclassical series against tgDHFR (selectivity ratio = 303.5) with excellent potency (28 nM). Analogue 11, also displayed significant selectivity for sfDHFR (selectivity ratio = 4902). Compound 22 was evaluated in vivo for the inhibition of the growth of T.gondii trophozoites in mice, where at 50 mg/kg orally, it demonstrated distinct prolongation of survival without toxicity. Compounds 11, 12 and 21-23 were evaluated as antitumor agents in the National Cancer Institutes preclinical in vitro screening program. Compounds 12, 22, and 23 showed GI50s for tumor growth inhibition in the 10 -6 - 10 -7 M range.
“…A similar methodology, involving base-catalyzed cyclization of 2,6-diamino-4-hydroxypyrimidine and nitromalonaldehyde, has been reported by Price et al. for the synthesis of the 2-amino-4-hydroxy-6-nitropyrido[2,3- d ]pyrimidine. 1 …”
Fifteen novel nonclassical and two classical 2,4-diamino-6-(benzylamino)pyrido[2,3-d]pyrimidine antifolates were synthesized as potential inhibitors of Pneumocystis carinii, (pc) Toxoplasma gondii, (tg) rat liver (rl), and human (h) recombinant dihydrofolate reductases (DHFR). These analogues lack a 5-methyl substitution which has been shown to be important for increased hDHFR inhibitory activity. In addition, they contain a reversal of the C9-N10 bridge present in folates and most antifolates. The synthesis of the compounds involved the reaction of 2,4,6-triaminopyrimidine with the sodium salt of nitromalonaldehyde to afford the key intermediate 2,4-diamino-6-nitropyrido[2,3-d]pyrimidine (7), in a single step. Reduction of 7 to the 2,4,6-triaminopyrido[2,3-d]pyrimidine (8), followed by reductive amination with the appropriate benzaldehydes or phenylacetaldehydes afforded the target compounds. N9 methylation of these analogues was carried out using formaldehyde and sodium cyanoborohydride. The analogues demonstrated significant inhibition of pcDHFR and tgDHFR. N9 methylation significantly increased DHFR inhibitory potency. Compound 11, the 3'4'5'-trimethoxy-substituted analogue with a selectivity ratio of 9.4 for tgDHFR (compared to rlDHFR) was the most selective analogue of the nonclassical series. Compound 22, the N9 methyl 2'5'-dimethoxy-substituted analogue was the most potent analogue against tgDHFR (IC 50 = 6.3 nM) and was the second most selective analogue for tgDHFR (compared to rlDHFR) in the nonclassical series. The naphthyl-substituted analogues 23-25 were generally more potent against rlDHFR than against pcDHFR and tgDHFR. Selected analogues were also evaluated against Streptococcus faecium (sf) DHFR, Escherichia coli (ec) DHFR, Lactobacillus casei (lc) DHFR and tgDHFR with hDHFR as the mammalian reference, under slightly different assay conditions than those employed for rlDHFR. Analogues 11 and 22 had selectivity ratios of greater than 100 for tgDHFR (compared to hDHFR). Analogue 22 in particular, was the most selective analogue of the nonclassical series against tgDHFR (selectivity ratio = 303.5) with excellent potency (28 nM). Analogue 11, also displayed significant selectivity for sfDHFR (selectivity ratio = 4902). Compound 22 was evaluated in vivo for the inhibition of the growth of T.gondii trophozoites in mice, where at 50 mg/kg orally, it demonstrated distinct prolongation of survival without toxicity. Compounds 11, 12 and 21-23 were evaluated as antitumor agents in the National Cancer Institutes preclinical in vitro screening program. Compounds 12, 22, and 23 showed GI50s for tumor growth inhibition in the 10 -6 - 10 -7 M range.
“…This material is considered unstable and potentially explosive requiring its immediate use in the following step. The second step is a condensation reaction of the nitromalonaldehyde onto the existing heterocyclic ring scaffold of 2,4-diamino-6-hydroxypyrimidine performed in the presence of aqueous base 13. This reaction produced the fused 2-ring heterocyclic, modified 6-nitro-5-deaza pterin as a sodium salt that was converted to free amide by boiling the salt in hydrochloric acid, which afforded the product 2 as fine orange-tan needles upon cooling.…”
The increasing emergence of resistant bacteria drives us to design and develop new antimicrobial agents. Pursuant to that goal, a new targeting approach of the dihydropteroate synthase enzyme, which serves as the site of action for the sulfonamide class of antimicrobial agents, is being explored. Using structural information, a new class of transition state mimics has been designed and synthesized that have the capacity to bind to the pterin, phosphate and para-amino binding sites. The design, synthesis and evaluation of these compounds as inhibitors of Bacillus anthracis dihydropteroate synthase is described herein. Outcomes from this work have identified the first trivalent inhibitors of dihydropteroate synthase whose activity displayed slow binding inhibition. The most active compounds in this series contained an oxidized pterin ring. The binding of these inhibitors was modeled into the dihydropteroate synthase active site and demonstrated a good correlation with the observed bioassay data, as well as provided important insight for the future design of higher affinity transition state mimics.
“…The use of tetramethylthiourea was necessary in order to prevent intramolecular cyclization to the thiazole [6]. The synthesis of 6-substituted-5-deazapurines via the condensation of 2,6-diamino-3H-pyrimidin-4-one with malonaldehydes has been reported for 2-nitromalonaldehyde [7], triformylmethane (2-formylmalonaldehyde) [8] and 2-bromomalonaldehyde [9]. In a similar manner malonaldehyde 4 condensed readily with 2,6-diamino-3H-pyrimidin-4-one under acidic conditions to give compound 5 in 85% yield.…”
The folate analogue, 9-thia-5,10-dideazafolic acid (3b), was obtained in an efficient two-step procedure in an overall yield of 60%. The previously unknown intermediate dimethyl-thiocarbamic acid S-(2-amino-3,4-dihydo-4-oxo-pyrido[2,3-d]pyrimidin-6-yl) ester (5) was prepared via the condensation of 2,6-diamino-3H-pyrimidin-4-one and S-(2-malonaldehyde)-1,1,3,3-tetramethylthiouronium bromide (4). Compound 5, in a one pot procedure, was deprotected using sodium hydroxide and then coupled to diethyl N- [(4-chloromethyl)benzoyl]-L-glutamate, followed by saponification of the ethyl esters to give the 9-thia-5,10-dideazafolic acid (3b). Compound 3b was a potent inhibitor of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (K i of 8 ± 5 µM) and showed no inhibition of human glycinamide ribonucleotide transformylase at concentrations as high as 50 µM. Compound 3b was screened by the National Cancer Institute Developmental Therapeutics Program against 60 human tumors and was found to be active against a leukemia RPMI-8226 cell line where the LC 50 was 1 µM.
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