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

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Rosowsky A, Papoulis AT, Queener SF

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

J Med Chem. 1998 Mar 12;41(6):913-8.

PubMed ID
9526565 [ View in PubMed
]
Abstract

Three previously unreported (R,S)-2,4-diamino-5-[(3,4,5-trimethoxyphenyl) alkyl]-6,7-dihydro-5H-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 microM, respectively, against P. carinii DHFR, as compared to 12 microM for TMP. Against the T. gondii enzyme, 15a-c had IC50 values of 21, 0.14 and 0.14 microM, respectively, as compared to 2.7 microM 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-dihydro-5H-cyclopenta[d]pyrimidines with a classical p-aminobenzoyl-L-glutamate side chain as inhibitors of bovine, murine, and human DHFR.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PiritreximDihydrofolate reductaseIC 50 (nM)31N/AN/ADetails
PiritreximDihydrofolate reductaseIC 50 (nM)17N/AN/ADetails
PyrimethamineDihydrofolate reductaseIC 50 (nM)390N/AN/ADetails
PyrimethamineDihydrofolate reductaseIC 50 (nM)2400N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)2700N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)12000N/AN/ADetails
TrimetrexateDihydrofolate reductaseIC 50 (nM)42N/AN/ADetails
TrimetrexateDihydrofolate reductaseIC 50 (nM)10N/AN/ADetails