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Literature summary extracted from

  • Linciano, P.; Cullia, G.; Borsari, C.; Santucci, M.; Ferrari, S.; Witt, G.; Gul, S.; Kuzikov, M.; Ellinger, B.; Santarem, N.; Cordeiro da Silva, A.; Conti, P.; Bolognesi, M.L.; Roberti, M.; Prati, F.; Bartoccini, F.; Retini, M.; Piersanti, G.; Cavalli, A.; Goldoni, L.; Bertozzi, S.M.; Bertozzi, F.; , B.
    Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign (2020), Eur. J. Med. Chem., 189, 112047 .
    View publication on PubMed

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.33 22-phenyl[11,21:24,31-terphenyl]-13,15,34-triol
-
 Leishmania major
1.5.1.33 22-phenyl[11,21:24,31-terphenyl]-13,15,34-triol
-
 Trypanosoma brucei brucei
1.5.1.33 4-(benzyloxy)pyrimidine-2,6-diamine LIB_66 Leishmania major
1.5.1.33 4-(benzyloxy)pyrimidine-2,6-diamine LIB_66 Trypanosoma brucei brucei
1.5.1.33 6,6'-[1,4-phenylenebis(methyleneazanediyl)]bis(N-benzylhexanamide)
-
 Leishmania major
1.5.1.33 6,6'-[1,4-phenylenebis(methyleneazanediyl)]bis(N-benzylhexanamide)
-
 Trypanosoma brucei brucei
1.5.1.33 6,6'-[methylenebis[(4,1-phenylene)methyleneazanediyl]]bis(N-benzylhexanamide)
-
 Leishmania major
1.5.1.33 6,6'-[methylenebis[(4,1-phenylene)methyleneazanediyl]]bis(N-benzylhexanamide)
-
 Trypanosoma brucei brucei
1.5.1.33 6,6'-[[1,1'-biphenyl]-4,4'-diylbis(methyleneazanediyl)]bis(N-benzylhexanamide)
-
 Leishmania major
1.5.1.33 6,6'-[[1,1'-biphenyl]-4,4'-diylbis(methyleneazanediyl)]bis(N-benzylhexanamide)
-
 Trypanosoma brucei brucei
1.5.1.33 6-[(3aR,9bS)-2,3,3a,9b-tetrahydro[1]benzopyrano[4,3-b]pyrrol-1(4H)-yl]hexan-1-amine
-
 Leishmania major
1.5.1.33 6-[(3aR,9bS)-2,3,3a,9b-tetrahydro[1]benzopyrano[4,3-b]pyrrol-1(4H)-yl]hexan-1-amine
-
 Trypanosoma brucei brucei
1.5.1.33 6-[(4-methoxyphenyl)methoxy]pyrimidine-2,4-diamine
-
 Leishmania major
1.5.1.33 6-[(4-methoxyphenyl)methoxy]pyrimidine-2,4-diamine
-
 Trypanosoma brucei brucei
1.5.1.33 9-methyl-2-(2-phenylethyl)-9H-purin-6-amine
-
 Leishmania major
1.5.1.33 9-methyl-2-(2-phenylethyl)-9H-purin-6-amine
-
 Trypanosoma brucei brucei
1.5.1.33 additional information identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign, screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1, NMR study, overview. Nine compounds are active against parasitic PTR1 and are selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified is 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, 6 different LIB_66 derivatives are synthesized to explore its structure-activity relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The compounds are more inhibitory against the enzyme from Trypanosoma brucei compared to the enzyme from Leishmania major. Docking study and molecular modelling Leishmania major
1.5.1.33 additional information identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign, screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1, NMR study, overview. Nine compounds are active against parasitic PTR1 and are selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified is 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, 6 different LIB_66 derivatives are synthesized to explore its structure-activity-relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The compounds are more inhibitory against the enzyme from Trypanosoma brucei compared to the enzyme from Leishmania major. Docking study and molecular modelling; N4,N6-dibenzylpyrimidine-2,4,6-triamine is not inhibitory Trypanosoma brucei brucei
1.5.1.33 N,N'-[tridecane-1,13-diylbis[(4,1-phenylene)methylene]]bis[1-(2-methoxyphenyl)methanamine]
-
 Leishmania major
1.5.1.33 N,N'-[tridecane-1,13-diylbis[(4,1-phenylene)methylene]]bis[1-(2-methoxyphenyl)methanamine]
-
 Trypanosoma brucei brucei
1.5.1.33 N1,N1-bis(4-fluorophenyl)-N2-(3-phenylpropyl)ethane-1,2-diamine
-
 Leishmania major
1.5.1.33 N1,N1-bis(4-fluorophenyl)-N2-(3-phenylpropyl)ethane-1,2-diamine
-
 Trypanosoma brucei brucei
1.5.1.33 N4,N6-dibenzylpyrimidine-2,4,6-triamine
-
 Leishmania major
1.5.1.33 N4-benzylpyrimidine-2,4,6-triamine
-
 Leishmania major
1.5.1.33 N4-benzylpyrimidine-2,4,6-triamine
-
 Trypanosoma brucei brucei
1.5.1.33 N4-[(4-fluorophenyl)methyl]pyrimidine-2,4,6-triamine
-
 Leishmania major
1.5.1.33 N4-[(4-fluorophenyl)methyl]pyrimidine-2,4,6-triamine
-
 Trypanosoma brucei brucei
1.5.1.33 N4-[(4-methoxyphenyl)methyl]pyrimidine-2,4,6-triamine
-
 Leishmania major
1.5.1.33 N4-[(4-methoxyphenyl)methyl]pyrimidine-2,4,6-triamine
-
 Trypanosoma brucei brucei
1.5.1.33 N4-[([1,1'-biphenyl]-4-yl)methyl]pyrimidine-2,4,6-triamine
-
 Leishmania major
1.5.1.33 N4-[([1,1'-biphenyl]-4-yl)methyl]pyrimidine-2,4,6-triamine
-
 Trypanosoma brucei brucei

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.5.1.33 biopterin + NADPH + H+ Leishmania major
-
 dihydrobiopterin + NADP+
-
 ?
1.5.1.33 biopterin + NADPH + H+ Trypanosoma brucei brucei
-
 dihydrobiopterin + NADP+
-
 ?
1.5.1.33 dihydrobiopterin + NADPH + H+ Leishmania major
-
 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?
1.5.1.33 dihydrobiopterin + NADPH + H+ Trypanosoma brucei brucei
-
 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?
1.5.1.33 additional information Leishmania major enzyme PTR1 synthesizes the formation of tetrahydrobiopterin from biopterin via dihydrobiopterin or from the quinoide form dihydrobiopterin, pathway overview ?
-
-
1.5.1.33 additional information Trypanosoma brucei brucei enzyme PTR1 synthesizes the formation of tetrahydrobiopterin from biopterin via dihydrobiopterin or from the quinoide form dihydrobiopterin, pathway overview ?
-
-

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.33 Leishmania major Q01782
-
-
1.5.1.33 Trypanosoma brucei brucei O76290
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.33 biopterin + NADPH + H+
-
 Leishmania major dihydrobiopterin + NADP+
-
 ?
1.5.1.33 biopterin + NADPH + H+
-
 Trypanosoma brucei brucei dihydrobiopterin + NADP+
-
 ?
1.5.1.33 dihydrobiopterin + NADPH + H+
-
 Leishmania major 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?
1.5.1.33 dihydrobiopterin + NADPH + H+
-
 Trypanosoma brucei brucei 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?
1.5.1.33 additional information enzyme PTR1 synthesizes the formation of tetrahydrobiopterin from biopterin via dihydrobiopterin or from the quinoide form dihydrobiopterin, pathway overview Leishmania major ?
-
-
1.5.1.33 additional information enzyme PTR1 synthesizes the formation of tetrahydrobiopterin from biopterin via dihydrobiopterin or from the quinoide form dihydrobiopterin, pathway overview Trypanosoma brucei brucei ?
-
-

Synonyms

EC Number Synonyms Comment Organism
1.5.1.33 LmPTR1
-
 Leishmania major
1.5.1.33 pteridine reductase 1
-
 Leishmania major
1.5.1.33 pteridine reductase 1
-
 Trypanosoma brucei brucei
1.5.1.33 PTR1
-
 Leishmania major
1.5.1.33 PTR1
-
 Trypanosoma brucei brucei
1.5.1.33 TbPTR1
-
 Trypanosoma brucei brucei

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.5.1.33 25
-
 assay at Leishmania major
1.5.1.33 25
-
 assay at Trypanosoma brucei brucei

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.5.1.33 7.4
-
 assay at Leishmania major
1.5.1.33 7.4
-
 assay at Trypanosoma brucei brucei

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.33 NADPH
-
 Leishmania major
1.5.1.33 NADPH
-
 Trypanosoma brucei brucei

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
1.5.1.33 0.0002
-
 N,N'-[tridecane-1,13-diylbis[(4,1-phenylene)methylene]]bis[1-(2-methoxyphenyl)methanamine] pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0002
-
 N4-[([1,1'-biphenyl]-4-yl)methyl]pyrimidine-2,4,6-triamine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0003
-
 N4-[(4-methoxyphenyl)methyl]pyrimidine-2,4,6-triamine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0006
-
 4-(benzyloxy)pyrimidine-2,6-diamine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0008
-
 6-[(4-methoxyphenyl)methoxy]pyrimidine-2,4-diamine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0011
-
 N4-[(4-fluorophenyl)methyl]pyrimidine-2,4,6-triamine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0016
-
 6,6'-[[1,1'-biphenyl]-4,4'-diylbis(methyleneazanediyl)]bis(N-benzylhexanamide) pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0016
-
 6-[(3aR,9bS)-2,3,3a,9b-tetrahydro[1]benzopyrano[4,3-b]pyrrol-1(4H)-yl]hexan-1-amine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0017
-
 6,6'-[1,4-phenylenebis(methyleneazanediyl)]bis(N-benzylhexanamide) pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0022
-
 N1,N1-bis(4-fluorophenyl)-N2-(3-phenylpropyl)ethane-1,2-diamine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0027
-
 6,6'-[methylenebis[(4,1-phenylene)methyleneazanediyl]]bis(N-benzylhexanamide) pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0034
-
 N4-benzylpyrimidine-2,4,6-triamine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0049
-
 9-methyl-2-(2-phenylethyl)-9H-purin-6-amine pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.0057
-
 22-phenyl[11,21:24,31-terphenyl]-13,15,34-triol pH 7.4, 25°C Leishmania major
1.5.1.33 0.01
-
 22-phenyl[11,21:24,31-terphenyl]-13,15,34-triol pH 7.4, 25°C Trypanosoma brucei brucei
1.5.1.33 0.012
-
 9-methyl-2-(2-phenylethyl)-9H-purin-6-amine pH 7.4, 25°C Leishmania major
1.5.1.33 0.0148
-
 6,6'-[methylenebis[(4,1-phenylene)methyleneazanediyl]]bis(N-benzylhexanamide) pH 7.4, 25°C Leishmania major
1.5.1.33 0.0153
-
 N4-[([1,1'-biphenyl]-4-yl)methyl]pyrimidine-2,4,6-triamine pH 7.4, 25°C Leishmania major
1.5.1.33 0.0192
-
 6,6'-[[1,1'-biphenyl]-4,4'-diylbis(methyleneazanediyl)]bis(N-benzylhexanamide) pH 7.4, 25°C Leishmania major
1.5.1.33 0.0372
-
 N,N'-[tridecane-1,13-diylbis[(4,1-phenylene)methylene]]bis[1-(2-methoxyphenyl)methanamine] pH 7.4, 25°C Leishmania major
1.5.1.33 0.0416
-
 N4-[(4-methoxyphenyl)methyl]pyrimidine-2,4,6-triamine pH 7.4, 25°C Leishmania major
1.5.1.33 0.1
-
 4-(benzyloxy)pyrimidine-2,6-diamine pH 7.4, 25°C Leishmania major
1.5.1.33 0.1
-
 6,6'-[1,4-phenylenebis(methyleneazanediyl)]bis(N-benzylhexanamide) pH 7.4, 25°C Leishmania major
1.5.1.33 0.1
-
 6-[(3aR,9bS)-2,3,3a,9b-tetrahydro[1]benzopyrano[4,3-b]pyrrol-1(4H)-yl]hexan-1-amine pH 7.4, 25°C Leishmania major
1.5.1.33 0.1
-
 6-[(4-methoxyphenyl)methoxy]pyrimidine-2,4-diamine pH 7.4, 25°C Leishmania major
1.5.1.33 0.1
-
 N1,N1-bis(4-fluorophenyl)-N2-(3-phenylpropyl)ethane-1,2-diamine pH 7.4, 25°C Leishmania major
1.5.1.33 0.1
-
 N4,N6-dibenzylpyrimidine-2,4,6-triamine pH 7.4, 25°C Leishmania major
1.5.1.33 0.1
-
 N4-benzylpyrimidine-2,4,6-triamine pH 7.4, 25°C Leishmania major
1.5.1.33 0.1
-
 N4-[(4-fluorophenyl)methyl]pyrimidine-2,4,6-triamine pH 7.4, 25°C Leishmania major