Effect of N9-Methylation and Bridge Atom Variation on the Activity of 5-Substituted 2,4-Diaminopyrrolo[2,3-d]pyrimidines against Dihydrofolate Reductases from Pneumocystis carinii and Toxoplasma gondii1a,b

Autor:	Aleem Gangjee, Sherry F. Queener, Farahnaz Mavandadi
Rok vydání:	1997
Předmět:	biology Bicyclic molecule Pyrimidine Stereochemistry Substituent Toxoplasma gondii Methylation biology.organism_classification Chemical synthesis chemistry.chemical_compound chemistry Pneumocystis carinii Drug Discovery Dihydrofolate reductase biology.protein Molecular Medicine
Zdroj:	Journal of Medicinal Chemistry. 40:1173-1177
ISSN:	1520-4804 0022-2623
DOI:	10.1021/jm960717q
Popis:	The effect of N9-methylation and bridge atom variation on inhibitory potency and selectivity of 2,4-diaminopyrrolo[2,3-d]pyrimidines against dihydrofolate reductases (DHFR) was studied. Specifically three nonclassical 2,4-diamino-5-((N-methylanilino)methyl)pyrrolo[2,3-d]pyrimidines with 2‘,5‘-dimethoxyphenyl (2), 3‘,4‘-dichlorophenyl (3), 1‘-naphthyl (4), one classical analogue with a 4‘-L-glutamate substituent (10), and four nonclassical 2,4-diamino-5-((phenylthio)methyl)pyrrolo[2,3-d]pyrimidines with 3‘,4‘-dimethoxyphenyl (5), 3‘,4‘-dichlorophenyl (6), 1‘-naphthyl (7), and 2‘-naphthyl (8) substituents were synthesized. The classical and nonclassical analogues were obtained by displacement of the intermediate 2,4-diamino-5-bromomethylpyrrolo[2,3-d]pyrimidine, 14, with appropriately substituted N-methylaniline, thiophenols, or 4-(N-methylamino)benzoyl-l-glutamate. Compounds 2−8 and 10 were evaluated against Pneumocystis carinii (pc), Toxoplasma gondii (tg), and rat liver (rl) DHFRs. The N-methyl and thiom...
Databáze:	OpenAIRE
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