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Literature summary extracted from

  • Gangjee, A.; Li, W.; Yang, J.; Kisliuk, R.L.
    Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors (2008), J. Med. Chem., 51, 68-76.
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
2.1.1.45 medicine inhibition of thymidylate synthase and DHFR enzymes has found clinical utility as antitumor, antimicrobial and antiprotozoal agents Homo sapiens
2.1.1.45 medicine inhibition of TS and DHFR enzymes has found clinical utility as antitumor, antimicrobial and antiprotozoal agent Toxoplasma gondii
2.1.1.45 medicine inhibition of TS and DHFR enzymes has found clinical utility as antitumor, antimicrobial and antiprotozoal agents Escherichia coli

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.3 2-amino-5-(4-bromobenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
 Toxoplasma gondii
1.5.1.3 2-amino-5-(4-chlorobenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
 Toxoplasma gondii
1.5.1.3 2-amino-5-(4-methoxybenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
 Toxoplasma gondii
1.5.1.3 2-amino-6-methyl-5-(4-nitrobenzyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
 Toxoplasma gondii
1.5.1.3 2-amino-6-methyl-5-[4-(trifluoromethoxy)benzyl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
 Toxoplasma gondii
1.5.1.3 methotrexate
-
 Homo sapiens
1.5.1.3 methotrexate
-
 Toxoplasma gondii
1.5.1.3 N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl)-L-glutamic acid dual inhibitor of both dihydrofolate reductase and thymidylate synthase. Inhibitory to Toxoplasma gondii dihydrofolate reductase, little inhibition of Escherichia coli enzyme Homo sapiens
1.5.1.3 N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl)-L-glutamic acid inhibitory to human dihydrofolate reductase, little inhibition of Escherichia coli enzyme Toxoplasma gondii
2.1.1.45 (2S)-2-[([4-[(2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)sulfanyl]phenyl]carbonyl)amino]pentanedioic acid dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Toxoplasma gondii enzyme Escherichia coli
2.1.1.45 (2S)-2-[([4-[(2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)sulfanyl]phenyl]carbonyl)amino]pentanedioic acid dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on Escherichia coli and Toxoplasma gondii enzyme Homo sapiens
2.1.1.45 10-propargyl-5,8-dideazafolate PDDF Escherichia coli
2.1.1.45 10-propargyl-5,8-dideazafolate PDDF Homo sapiens
2.1.1.45 10-propargyl-5,8-dideazafolate PDDF Toxoplasma gondii
2.1.1.45 N-(4-((2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo(3,2-d)pyrimidin-5-yl)methyl)benzoyl)-L-glutamic acid
-
 Escherichia coli
2.1.1.45 N-(4-((2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo(3,2-d)pyrimidin-5-yl)methyl)benzoyl)-L-glutamic acid
-
 Homo sapiens
2.1.1.45 N-(4-((2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo(3,2-d)pyrimidin-5-yl)methyl)benzoyl)-L-glutamic acid
-
 Toxoplasma gondii
2.1.1.45 N-(4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-5-yl)thio)benzoyl)-L-glutamic acid
-
 Escherichia coli
2.1.1.45 N-(4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-5-yl)thio)benzoyl)-L-glutamic acid
-
 Homo sapiens
2.1.1.45 N-(4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-5-yl)thio)benzoyl)-L-glutamic acid
-
 Toxoplasma gondii
2.1.1.45 N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl]-L-glutamic acid dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Escherichia coli enzyme; dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on human and Toxoplasma gondii enzyme Escherichia coli
2.1.1.45 N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl]-L-glutamic acid dual inhibitor of thymidylate synthase and dihydrofolate reductase. Comparison with inhibitory effect on Escherichia coli and Toxoplasma gondii enzyme Homo sapiens
2.1.1.45 pemetrexed
-
 Escherichia coli
2.1.1.45 pemetrexed
-
 Homo sapiens
2.1.1.45 pemetrexed
-
 Toxoplasma gondii

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP Escherichia coli
-
 7,8-dihydrofolate + dTMP
-
 ?
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP Homo sapiens
-
 7,8-dihydrofolate + dTMP
-
 ?
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP Toxoplasma gondii
-
 7,8-dihydrofolate + dTMP
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.3 Homo sapiens P00374
-
-
1.5.1.3 Toxoplasma gondii
-
-
-
2.1.1.45 Escherichia coli
-
-
-
2.1.1.45 Homo sapiens
-
-
-
2.1.1.45 Toxoplasma gondii
-
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP
-
 Escherichia coli 7,8-dihydrofolate + dTMP
-
 ?
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP
-
 Homo sapiens 7,8-dihydrofolate + dTMP
-
 ?
2.1.1.45 5,10-methylenetetrahydrofolate + dUMP
-
 Toxoplasma gondii 7,8-dihydrofolate + dTMP
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.1.1.45 TS-DHFR
-
 Escherichia coli
2.1.1.45 TS-DHFR
-
 Homo sapiens
2.1.1.45 TS-DHFR
-
 Toxoplasma gondii

Cofactor

EC Number Cofactor Comment Organism Structure
2.1.1.45 methenyltetrahydrofolate
-
 Escherichia coli
2.1.1.45 methenyltetrahydrofolate
-
 Homo sapiens
2.1.1.45 methenyltetrahydrofolate
-
 Toxoplasma gondii

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
1.5.1.3 0.00002
-
 37°C Homo sapiens methotrexate
1.5.1.3 0.000023
-
 37°C Toxoplasma gondii N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl)-L-glutamic acid
1.5.1.3 0.000033
-
 37°C Toxoplasma gondii methotrexate
1.5.1.3 0.00012
-
 37°C Homo sapiens N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl)-L-glutamic acid
1.5.1.3 0.00027
-
-
 Toxoplasma gondii 2-amino-5-(4-bromobenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
1.5.1.3 0.0003
-
-
 Toxoplasma gondii 2-amino-6-methyl-5-[4-(trifluoromethoxy)benzyl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
1.5.1.3 0.00033
-
-
 Toxoplasma gondii 2-amino-6-methyl-5-(4-nitrobenzyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
1.5.1.3 0.00035
-
-
 Toxoplasma gondii 2-amino-5-(4-chlorobenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
1.5.1.3 0.0035
-
-
 Toxoplasma gondii 2-amino-5-(4-methoxybenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
2.1.1.45 0.000019
-
-
 Escherichia coli 10-propargyl-5,8-dideazafolate
2.1.1.45 0.000046
-
-
 Homo sapiens N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl]-L-glutamic acid
2.1.1.45 0.000046
-
 potent dual inhibitor of human TS and human DHFR, 2-fold more potent than PDDF and 206-fold more potent than pemetrexed Homo sapiens N-(4-((2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo(3,2-d)pyrimidin-5-yl)methyl)benzoyl)-L-glutamic acid
2.1.1.45 0.000054
-
-
 Homo sapiens (2S)-2-[([4-[(2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)sulfanyl]phenyl]carbonyl)amino]pentanedioic acid
2.1.1.45 0.000054
-
 potent inhibitor of human TS and moderate inhibitor of human DHFR Homo sapiens N-(4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-5-yl)thio)benzoyl)-L-glutamic acid
2.1.1.45 0.000069
-
-
 Escherichia coli N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl]-L-glutamic acid
2.1.1.45 0.000069
-
 potent inhibitor of human TS Escherichia coli N-(4-((2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo(3,2-d)pyrimidin-5-yl)methyl)benzoyl)-L-glutamic acid
2.1.1.45 0.000085
-
-
 Homo sapiens 10-propargyl-5,8-dideazafolate
2.1.1.45 0.00023
-
-
 Escherichia coli N-[4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl]-L-glutamic acid
2.1.1.45 0.00023
-
 moderate inhibitor of human thymidylate synthase Toxoplasma gondii N-(4-((2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo(3,2-d)pyrimidin-5-yl)methyl)benzoyl)-L-glutamic acid
2.1.1.45 0.00027
-
-
 Escherichia coli (2S)-2-[([4-[(2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)sulfanyl]phenyl]carbonyl)amino]pentanedioic acid
2.1.1.45 0.00027
-
 moderate inhibitor of human TS Escherichia coli N-(4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-5-yl)thio)benzoyl)-L-glutamic acid
2.1.1.45 0.00043
-
-
 Toxoplasma gondii 10-propargyl-5,8-dideazafolate
2.1.1.45 0.0028
-
-
 Toxoplasma gondii pemetrexed
2.1.1.45 0.0095
-
-
 Homo sapiens pemetrexed
2.1.1.45 0.076
-
-
 Escherichia coli pemetrexed