Brominated trimetrexate analogues as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase

Andre Rosowsky, Clara E. Mota, Sherry F. Queener

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Five previously undescribed trimetrexate analogues with bulky 2'-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,1-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2'-bromo-3',4',5'-trimethoxybenzyl)-4-methylthiophene-3-car bonitrile (15) and 2-amino-4-[2-(2'-bromo-3',4',5'-trimethoxyphenyl)ethyl]thiophene-3-car bonitrile (16). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2'-bromo-3',4',5'-trimethoxybenzyl)-4-methylthieno[2,3- d]pyrimidine (8a) and 2,4-diamino-4[2-(2'-bromo-3',4',5'-trimethoxyphenyl)ethylthieno[2,3-d] pyrimidine (12) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxyamilinomethyl)-5-chloroquin azoline (9a), 2,4-diamino-5-(2'-bromo-3',4',5'-trimethoxyanilinomethyl)quinazoline (10), and 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxyanilinomethyl)quinazoline (11). Enzyme inhibition assays revealed that space-filling 2'-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3',4',5'-trimethoxyphenyl side chain and a CH2, CH2CH2, or CH2NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.

Original languageEnglish (US)
Pages (from-to)1959-1966
Number of pages8
JournalJournal of Heterocyclic Chemistry
Volume33
Issue number6
DOIs
StatePublished - Jan 1 1996

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Trimetrexate
Tetrahydrofolate Dehydrogenase
Quinazolines
Substitution reactions
Railroad cars
Enzyme inhibition
Thiophenes
Chloroquine
Sulfur
Liver
Rats
Condensation
Assays
pyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Brominated trimetrexate analogues as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. / Rosowsky, Andre; Mota, Clara E.; Queener, Sherry F.

In: Journal of Heterocyclic Chemistry, Vol. 33, No. 6, 01.01.1996, p. 1959-1966.

Research output: Contribution to journalArticle

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title = "Brominated trimetrexate analogues as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase",
abstract = "Five previously undescribed trimetrexate analogues with bulky 2'-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,1-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2'-bromo-3',4',5'-trimethoxybenzyl)-4-methylthiophene-3-car bonitrile (15) and 2-amino-4-[2-(2'-bromo-3',4',5'-trimethoxyphenyl)ethyl]thiophene-3-car bonitrile (16). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2'-bromo-3',4',5'-trimethoxybenzyl)-4-methylthieno[2,3- d]pyrimidine (8a) and 2,4-diamino-4[2-(2'-bromo-3',4',5'-trimethoxyphenyl)ethylthieno[2,3-d] pyrimidine (12) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxyamilinomethyl)-5-chloroquin azoline (9a), 2,4-diamino-5-(2'-bromo-3',4',5'-trimethoxyanilinomethyl)quinazoline (10), and 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxyanilinomethyl)quinazoline (11). Enzyme inhibition assays revealed that space-filling 2'-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3',4',5'-trimethoxyphenyl side chain and a CH2, CH2CH2, or CH2NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.",
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N2 - Five previously undescribed trimetrexate analogues with bulky 2'-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,1-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2'-bromo-3',4',5'-trimethoxybenzyl)-4-methylthiophene-3-car bonitrile (15) and 2-amino-4-[2-(2'-bromo-3',4',5'-trimethoxyphenyl)ethyl]thiophene-3-car bonitrile (16). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2'-bromo-3',4',5'-trimethoxybenzyl)-4-methylthieno[2,3- d]pyrimidine (8a) and 2,4-diamino-4[2-(2'-bromo-3',4',5'-trimethoxyphenyl)ethylthieno[2,3-d] pyrimidine (12) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxyamilinomethyl)-5-chloroquin azoline (9a), 2,4-diamino-5-(2'-bromo-3',4',5'-trimethoxyanilinomethyl)quinazoline (10), and 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxyanilinomethyl)quinazoline (11). Enzyme inhibition assays revealed that space-filling 2'-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3',4',5'-trimethoxyphenyl side chain and a CH2, CH2CH2, or CH2NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.

AB - Five previously undescribed trimetrexate analogues with bulky 2'-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,1-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2'-bromo-3',4',5'-trimethoxybenzyl)-4-methylthiophene-3-car bonitrile (15) and 2-amino-4-[2-(2'-bromo-3',4',5'-trimethoxyphenyl)ethyl]thiophene-3-car bonitrile (16). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2'-bromo-3',4',5'-trimethoxybenzyl)-4-methylthieno[2,3- d]pyrimidine (8a) and 2,4-diamino-4[2-(2'-bromo-3',4',5'-trimethoxyphenyl)ethylthieno[2,3-d] pyrimidine (12) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxyamilinomethyl)-5-chloroquin azoline (9a), 2,4-diamino-5-(2'-bromo-3',4',5'-trimethoxyanilinomethyl)quinazoline (10), and 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxyanilinomethyl)quinazoline (11). Enzyme inhibition assays revealed that space-filling 2'-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3',4',5'-trimethoxyphenyl side chain and a CH2, CH2CH2, or CH2NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.

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