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

A. Gangjee, F. Mavandadi, Sherry Queener

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The effect of N9-mathylation 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 analogies 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)benzeyl-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 analognes 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.

Original languageEnglish (US)
Pages (from-to)1173-1177
Number of pages5
JournalJournal of Medicinal Chemistry
Volume40
Issue number7
DOIs
StatePublished - 1997
Externally publishedYes

Fingerprint

Pneumocystis carinii
Pyrimidines
Tetrahydrofolate Dehydrogenase
Methylation
Toxoplasma
Glutamic Acid
Trimetrexate
Atoms
Liver
Rats
Pyrrolo(2,3-d)pyrimidine
methylaniline
pyrimidine
thiophenol

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{bdeb46669aad4f80af53528310b9c822,
title = "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",
abstract = "The effect of N9-mathylation 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 analogies 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)benzeyl-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 analognes 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.",
author = "A. Gangjee and F. Mavandadi and Sherry Queener",
year = "1997",
doi = "10.1021/jm960717q",
language = "English (US)",
volume = "40",
pages = "1173--1177",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - 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

AU - Gangjee, A.

AU - Mavandadi, F.

AU - Queener, Sherry

PY - 1997

Y1 - 1997

N2 - The effect of N9-mathylation 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 analogies 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)benzeyl-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 analognes 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.

AB - The effect of N9-mathylation 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 analogies 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)benzeyl-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 analognes 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.

UR - http://www.scopus.com/inward/record.url?scp=0030610833&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030610833&partnerID=8YFLogxK

U2 - 10.1021/jm960717q

DO - 10.1021/jm960717q

M3 - Article

VL - 40

SP - 1173

EP - 1177

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -