2,4-Diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine analogues of trimethoprim as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase

Andre Rosowsky, Andrew T. Papoulis, Sherry Queener

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28 Citations (Scopus)

Abstract

Three previously unreported (R,S)-2,4-diamino-5-[(3,4,5- trimethoxyphenyl)alkryl]-6,7-dihydro5H-cyclopenta[d]pyrimidines 15a-c were synthesized as analogues of trimethoprim (TMP) and were tested as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase (DHFR). The length of the alkyl bridge between the cyclopenta[d]pyrimidine and trimethoxyphenyl moiety ranged from one in 15a to three carbons in 15c. The products were tested as competitive inhibitors of the reduction of dihydrofolate by Pneumocystis carinii, Toxoplasma gondii, and rat liver DHFR. Compounds 15a-c had IC50 values of >32, 1.8 and 1.3 μM, respectively, against P. carinii DHF, as compared to 12 μM for TMP. Against the T. gondii enzyme; 15a-c had IC50 values of 21, 0.14 and 0.14 μM, respectively, as compared to 2.7 μM for TMP. Inhibitors 15b and 15c with two- and three-carbon bridges were significantly more potent than 15a against all three enzymes. Unlike TMP, 15b and 15c were better inhibitors of the rat liver enzyme than of the microbial enzymes. The potency of 15b and 15c against rat liver DHFR was less than has been reported for the corresponding 6,7-dihydro5H-cyclopenta[d]pyrimidines with a classical p- aminobenzoyl-L-glutamate side chain as inhibitors of bovine, murine, and human DHFR.

Original languageEnglish
Pages (from-to)913-918
Number of pages6
JournalJournal of Medicinal Chemistry
Volume41
Issue number6
DOIs
StatePublished - Mar 12 1998

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Pneumocystis carinii
Tetrahydrofolate Dehydrogenase
Trimethoprim
Toxoplasma
Liver
Rats
Pyrimidines
Carbon
Enzymes
Inhibitory Concentration 50
Glutamic Acid
pyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

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title = "2,4-Diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine analogues of trimethoprim as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase",
abstract = "Three previously unreported (R,S)-2,4-diamino-5-[(3,4,5- trimethoxyphenyl)alkryl]-6,7-dihydro5H-cyclopenta[d]pyrimidines 15a-c were synthesized as analogues of trimethoprim (TMP) and were tested as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase (DHFR). The length of the alkyl bridge between the cyclopenta[d]pyrimidine and trimethoxyphenyl moiety ranged from one in 15a to three carbons in 15c. The products were tested as competitive inhibitors of the reduction of dihydrofolate by Pneumocystis carinii, Toxoplasma gondii, and rat liver DHFR. Compounds 15a-c had IC50 values of >32, 1.8 and 1.3 μM, respectively, against P. carinii DHF, as compared to 12 μM for TMP. Against the T. gondii enzyme; 15a-c had IC50 values of 21, 0.14 and 0.14 μM, respectively, as compared to 2.7 μM for TMP. Inhibitors 15b and 15c with two- and three-carbon bridges were significantly more potent than 15a against all three enzymes. Unlike TMP, 15b and 15c were better inhibitors of the rat liver enzyme than of the microbial enzymes. The potency of 15b and 15c against rat liver DHFR was less than has been reported for the corresponding 6,7-dihydro5H-cyclopenta[d]pyrimidines with a classical p- aminobenzoyl-L-glutamate side chain as inhibitors of bovine, murine, and human DHFR.",
author = "Andre Rosowsky and Papoulis, {Andrew T.} and Sherry Queener",
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T1 - 2,4-Diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine analogues of trimethoprim as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase

AU - Rosowsky, Andre

AU - Papoulis, Andrew T.

AU - Queener, Sherry

PY - 1998/3/12

Y1 - 1998/3/12

N2 - Three previously unreported (R,S)-2,4-diamino-5-[(3,4,5- trimethoxyphenyl)alkryl]-6,7-dihydro5H-cyclopenta[d]pyrimidines 15a-c were synthesized as analogues of trimethoprim (TMP) and were tested as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase (DHFR). The length of the alkyl bridge between the cyclopenta[d]pyrimidine and trimethoxyphenyl moiety ranged from one in 15a to three carbons in 15c. The products were tested as competitive inhibitors of the reduction of dihydrofolate by Pneumocystis carinii, Toxoplasma gondii, and rat liver DHFR. Compounds 15a-c had IC50 values of >32, 1.8 and 1.3 μM, respectively, against P. carinii DHF, as compared to 12 μM for TMP. Against the T. gondii enzyme; 15a-c had IC50 values of 21, 0.14 and 0.14 μM, respectively, as compared to 2.7 μM for TMP. Inhibitors 15b and 15c with two- and three-carbon bridges were significantly more potent than 15a against all three enzymes. Unlike TMP, 15b and 15c were better inhibitors of the rat liver enzyme than of the microbial enzymes. The potency of 15b and 15c against rat liver DHFR was less than has been reported for the corresponding 6,7-dihydro5H-cyclopenta[d]pyrimidines with a classical p- aminobenzoyl-L-glutamate side chain as inhibitors of bovine, murine, and human DHFR.

AB - Three previously unreported (R,S)-2,4-diamino-5-[(3,4,5- trimethoxyphenyl)alkryl]-6,7-dihydro5H-cyclopenta[d]pyrimidines 15a-c were synthesized as analogues of trimethoprim (TMP) and were tested as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase (DHFR). The length of the alkyl bridge between the cyclopenta[d]pyrimidine and trimethoxyphenyl moiety ranged from one in 15a to three carbons in 15c. The products were tested as competitive inhibitors of the reduction of dihydrofolate by Pneumocystis carinii, Toxoplasma gondii, and rat liver DHFR. Compounds 15a-c had IC50 values of >32, 1.8 and 1.3 μM, respectively, against P. carinii DHF, as compared to 12 μM for TMP. Against the T. gondii enzyme; 15a-c had IC50 values of 21, 0.14 and 0.14 μM, respectively, as compared to 2.7 μM for TMP. Inhibitors 15b and 15c with two- and three-carbon bridges were significantly more potent than 15a against all three enzymes. Unlike TMP, 15b and 15c were better inhibitors of the rat liver enzyme than of the microbial enzymes. The potency of 15b and 15c against rat liver DHFR was less than has been reported for the corresponding 6,7-dihydro5H-cyclopenta[d]pyrimidines with a classical p- aminobenzoyl-L-glutamate side chain as inhibitors of bovine, murine, and human DHFR.

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