| 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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MedLine Citation:
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PMID: 9526565 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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A Rosowsky; A T Papoulis; S F Queener |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 41 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1998 Mar |
Date Detail:
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Created Date: 1998-04-16 Completed Date: 1998-04-16 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 913-8 Citation Subset: IM |
Affiliation:
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Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Folic Acid Antagonists / chemical synthesis, pharmacology* Liver / drug effects, enzymology Pneumocystis / drug effects, enzymology* Pyrimidines / chemical synthesis, pharmacology* Rats Tetrahydrofolate Dehydrogenase / metabolism* Toxoplasma / drug effects, enzymology* Trimethoprim / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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N01-AI35171/AI/NIAID NIH HHS; R01-AI29904/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/2,4-diamino-5-(2-(3,4,5-trimethoxyphenyl)ethyl)-6,7-dihydro-5H-cyclopenta(d)pyrimidine; 0/2,4-diamino-5-(3,4,5-trimethoxybenzyl)-6,7-dihydro-5H-cyclopenta(d)pyrimidine; 0/2,4-diamino-5-(3-(3,4,5-trimethoxyphenyl)propyl)-5H-6,7-dihydrocyclopenta(d)pyrimidine; 0/Folic Acid Antagonists; 0/Pyrimidines; 738-70-5/Trimethoprim; EC 1.5.1.3/Tetrahydrofolate Dehydrogenase |
| Comments/Corrections | |
Erratum In:
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J Med Chem 2002 Apr 25;45(9):1957 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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