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Literature summary for 1.5.1.33 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
Search for more literature for 1.5.1.33

Inhibitors

Inhibitors Comment Organism Structure
22-phenyl[11,21:24,31-terphenyl]-13,15,34-triol
-
 Leishmania major
22-phenyl[11,21:24,31-terphenyl]-13,15,34-triol
-
 Trypanosoma brucei brucei
4-(benzyloxy)pyrimidine-2,6-diamine LIB_66 Leishmania major
4-(benzyloxy)pyrimidine-2,6-diamine LIB_66 Trypanosoma brucei brucei
6,6'-[1,4-phenylenebis(methyleneazanediyl)]bis(N-benzylhexanamide)
-
 Leishmania major
6,6'-[1,4-phenylenebis(methyleneazanediyl)]bis(N-benzylhexanamide)
-
 Trypanosoma brucei brucei
6,6'-[methylenebis[(4,1-phenylene)methyleneazanediyl]]bis(N-benzylhexanamide)
-
 Leishmania major
6,6'-[methylenebis[(4,1-phenylene)methyleneazanediyl]]bis(N-benzylhexanamide)
-
 Trypanosoma brucei brucei
6,6'-[[1,1'-biphenyl]-4,4'-diylbis(methyleneazanediyl)]bis(N-benzylhexanamide)
-
 Leishmania major
6,6'-[[1,1'-biphenyl]-4,4'-diylbis(methyleneazanediyl)]bis(N-benzylhexanamide)
-
 Trypanosoma brucei brucei
6-[(3aR,9bS)-2,3,3a,9b-tetrahydro[1]benzopyrano[4,3-b]pyrrol-1(4H)-yl]hexan-1-amine
-
 Leishmania major
6-[(3aR,9bS)-2,3,3a,9b-tetrahydro[1]benzopyrano[4,3-b]pyrrol-1(4H)-yl]hexan-1-amine
-
 Trypanosoma brucei brucei
6-[(4-methoxyphenyl)methoxy]pyrimidine-2,4-diamine
-
 Leishmania major
6-[(4-methoxyphenyl)methoxy]pyrimidine-2,4-diamine
-
 Trypanosoma brucei brucei
9-methyl-2-(2-phenylethyl)-9H-purin-6-amine
-
 Leishmania major
9-methyl-2-(2-phenylethyl)-9H-purin-6-amine
-
 Trypanosoma brucei brucei
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
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
N,N'-[tridecane-1,13-diylbis[(4,1-phenylene)methylene]]bis[1-(2-methoxyphenyl)methanamine]
-
 Leishmania major
N,N'-[tridecane-1,13-diylbis[(4,1-phenylene)methylene]]bis[1-(2-methoxyphenyl)methanamine]
-
 Trypanosoma brucei brucei
N1,N1-bis(4-fluorophenyl)-N2-(3-phenylpropyl)ethane-1,2-diamine
-
 Leishmania major
N1,N1-bis(4-fluorophenyl)-N2-(3-phenylpropyl)ethane-1,2-diamine
-
 Trypanosoma brucei brucei
N4,N6-dibenzylpyrimidine-2,4,6-triamine
-
 Leishmania major
N4-benzylpyrimidine-2,4,6-triamine
-
 Leishmania major
N4-benzylpyrimidine-2,4,6-triamine
-
 Trypanosoma brucei brucei
N4-[(4-fluorophenyl)methyl]pyrimidine-2,4,6-triamine
-
 Leishmania major
N4-[(4-fluorophenyl)methyl]pyrimidine-2,4,6-triamine
-
 Trypanosoma brucei brucei
N4-[(4-methoxyphenyl)methyl]pyrimidine-2,4,6-triamine
-
 Leishmania major
N4-[(4-methoxyphenyl)methyl]pyrimidine-2,4,6-triamine
-
 Trypanosoma brucei brucei
N4-[([1,1'-biphenyl]-4-yl)methyl]pyrimidine-2,4,6-triamine
-
 Leishmania major
N4-[([1,1'-biphenyl]-4-yl)methyl]pyrimidine-2,4,6-triamine
-
 Trypanosoma brucei brucei

Natural Substrates/ Products (Substrates)

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

Organism UniProt Comment Textmining
Leishmania major Q01782
-
-
Trypanosoma brucei brucei O76290
-
-

Substrates and Products (Substrate)

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

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

Temperature Optimum [°C]

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

pH Optimum

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

Cofactor

Cofactor Comment Organism Structure
NADPH
-
 Leishmania major
NADPH
-
 Trypanosoma brucei brucei

Ki Value [mM]

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