Document Detail

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 gondii.
MedLine Citation:
PMID:  9089339     Owner:  NLM     Status:  MEDLINE    
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 thiomethyl analogues were more inhibitory than their corresponding anilinomethyl analogues (previously reported) against all three DHFRs. The inhibitory potency of these analogues was greater against rlDHFR than against tgDHFR which resulted in a loss of selectivity for tgDHFR compared to the N9-H analogues. The classical N9-methyl analogue 10 was more potent and about 2-fold more selective against tgDHFR than its corresponding desmethyl analogue. All of the analogues, 2-8 and 10, were more selective than trimetrexate (TMQ) against pcDHFR (except 4) and significantly more selective than TMQ against tgDHFR.
A Gangjee; F Mavandadi; S F Queener
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  40     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1997 Mar 
Date Detail:
Created Date:  1997-05-01     Completed Date:  1997-05-01     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1173-7     Citation Subset:  IM    
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
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MeSH Terms
Enzyme Inhibitors / chemistry,  pharmacology*
Folic Acid Antagonists / chemistry,  pharmacology*
Liver / enzymology
Magnetic Resonance Spectroscopy
Pneumocystis / enzymology*
Pyrimidines / chemistry,  pharmacology*
Tetrahydrofolate Dehydrogenase / drug effects*
Toxoplasma / enzymology*
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Folic Acid Antagonists; 0/Pyrimidines; EC Dehydrogenase

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