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Literature summary for 2.1.2.1 extracted from

  • Witschel, M.C.; Rottmann, M.; Schwab, A.; Leartsakulpanich, U.; Chitnumsub, P.; Seet, M.; Tonazzi, S.; Schwertz, G.; Stelzer, F.; Mietzner, T.; McNamara, C.; Thater, F.; Freymond, C.; Jaruwat, A.; Pinthong, C.; Riangrungroj, P.; Oufir, M.; Hamburger, M.; Maeser, P.; Sanz-Alonso, L.M.; Charman, S.
    Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT) cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities (2015), J. Med. Chem., 58, 3117-3130 .
    View publication on PubMed
Search for more literature for 2.1.2.1

Crystallization (Commentary)

Crystallization (Comment) Organism
in complex with inhibitor, microbatch method, using 20-24% (w/v) PEG 4000, 0.06-0.12 M NaCl, 0.1 M Tris-HCl buffer, pH 8.5, and 10% (v/v) trifluoroethanol Plasmodium vivax

Inhibitors

Inhibitors Comment Organism Structure
(+/-)-methyl 5-[3-(6-amino-5-cyano-4-isopropyl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazol-4-yl)-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium berghei
(4R)-6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium falciparum
(4R)-6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium vivax
(4R,4S)-5-cyano-4-(3-cyano-5-[5-[((S)-1,3-dicarboxypropyl)-carbamoyl]thiophen-2-yl]phenyl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-6-aminium trifluoroacetate
-
 Plasmodium falciparum
(4R,4S)-5-cyano-4-(3-cyano-5-[5-[((S)-1,3-dicarboxypropyl)-carbamoyl]thiophen-2-yl]phenyl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-6-aminium trifluoroacetate
-
 Plasmodium vivax
(4S)-6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium falciparum
(4S)-6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium vivax
3'-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5'-cyano[1,1'-biphenyl]-3-carboxylic acid
-
 Plasmodium falciparum
3'-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5'-cyano[1,1'-biphenyl]-3-carboxylic acid
-
 Plasmodium vivax
5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]-N,N-dimethylthiophene-2-carboxamide
-
 Plasmodium falciparum
5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]-N,N-dimethylthiophene-2-carboxamide
-
 Plasmodium vivax
5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]-N-[3-(diethylamino)propyl]thiophene-2-carboxamide
-
 Plasmodium falciparum
5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]-N-[3-(diethylamino)propyl]thiophene-2-carboxamide
-
 Plasmodium vivax
5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylic acid
-
 Plasmodium falciparum
5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylic acid
-
 Plasmodium vivax
6-amino-3-methyl-4-[3-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium falciparum
6-amino-3-methyl-4-[3-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium vivax
6-amino-4-(3,5-dichlorophenyl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium falciparum
6-amino-4-(3,5-dichlorophenyl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium vivax
6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium falciparum
6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium vivax
6-amino-4-[3-cyano-5-(piperazin-1-yl)phenyl]-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitril
-
 Plasmodium falciparum
6-amino-4-[3-cyano-5-(piperazin-1-yl)phenyl]-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Plasmodium vivax
6-amino-5-cyano-4-[3-cyano-5-(5-[[3-(morpholin-4-ium-4-yl)propyl]carbamoyl]thiophen-2-yl)phenyl]-3-methyl-4-isopropyl-2,4-dihydropyrano[2,3-c]pyrazol-1-ium bis-(trifluoroacetate)
-
 Plasmodium falciparum
6-amino-5-cyano-4-[3-cyano-5-(5-[[3-(morpholin-4-ium-4-yl)propyl]carbamoyl]thiophen-2-yl)phenyl]-3-methyl-4-isopropyl-2,4-dihydropyrano[2,3-c]pyrazol-1-ium bis-(trifluoroacetate)
-
 Plasmodium vivax
benzyl 4-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]piperazine-1-carboxylate
-
 Plasmodium falciparum
benzyl 4-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]piperazine-1-carboxylate
-
 Plasmodium vivax
benzyl 5-[3-[(4R)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium falciparum
benzyl 5-[3-[(4R)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium vivax
benzyl 5-[3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium falciparum
benzyl 5-[3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium vivax
benzyl 5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium falciparum
benzyl 5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium vivax
ethyl 4-[[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl](methyl)amino]butanoate
-
 Plasmodium falciparum
ethyl 4-[[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl](methyl)amino]butanoate
-
 Plasmodium vivax
methyl 3'-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5'-chloro[1,1'-biphenyl]-4-carboxylate
-
 Plasmodium falciparum
methyl 3'-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5'-chloro[1,1'-biphenyl]-4-carboxylate
-
 Plasmodium vivax
methyl 5-[3-[(4R)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium falciparum
methyl 5-[3-[(4R)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium vivax
methyl 5-[3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium falciparum
methyl 5-[3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium vivax
methyl 5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
-
 Plasmodium falciparum

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
5,10-methylenetetrahydrofolate + glycine + H2O Plasmodium falciparum
-
 tetrahydrofolate + L-serine
-
 r
5,10-methylenetetrahydrofolate + glycine + H2O Plasmodium berghei
-
 tetrahydrofolate + L-serine
-
 r
5,10-methylenetetrahydrofolate + glycine + H2O Plasmodium vivax
-
 tetrahydrofolate + L-serine
-
 r
5,10-methylenetetrahydrofolate + glycine + H2O Plasmodium vivax Salvador I
-
 tetrahydrofolate + L-serine
-
 r
tetrahydrofolate + L-serine Plasmodium falciparum
-
 5,10-methylenetetrahydrofolate + glycine + H2O
-
 r
tetrahydrofolate + L-serine Plasmodium berghei
-
 5,10-methylenetetrahydrofolate + glycine + H2O
-
 r
tetrahydrofolate + L-serine Plasmodium vivax
-
 5,10-methylenetetrahydrofolate + glycine + H2O
-
 r
tetrahydrofolate + L-serine Plasmodium vivax Salvador I
-
 5,10-methylenetetrahydrofolate + glycine + H2O
-
 r

Organism

Organism UniProt Comment Textmining
Plasmodium berghei
-
-
-
Plasmodium falciparum
-
-
-
Plasmodium vivax A5K8L9
-
-
Plasmodium vivax Salvador I A5K8L9
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
5,10-methylenetetrahydrofolate + glycine + H2O
-
 Plasmodium falciparum tetrahydrofolate + L-serine
-
 r
5,10-methylenetetrahydrofolate + glycine + H2O
-
 Plasmodium berghei tetrahydrofolate + L-serine
-
 r
5,10-methylenetetrahydrofolate + glycine + H2O
-
 Plasmodium vivax tetrahydrofolate + L-serine
-
 r
5,10-methylenetetrahydrofolate + glycine + H2O
-
 Plasmodium vivax Salvador I tetrahydrofolate + L-serine
-
 r
tetrahydrofolate + L-serine
-
 Plasmodium falciparum 5,10-methylenetetrahydrofolate + glycine + H2O
-
 r
tetrahydrofolate + L-serine
-
 Plasmodium berghei 5,10-methylenetetrahydrofolate + glycine + H2O
-
 r
tetrahydrofolate + L-serine
-
 Plasmodium vivax 5,10-methylenetetrahydrofolate + glycine + H2O
-
 r
tetrahydrofolate + L-serine
-
 Plasmodium vivax Salvador I 5,10-methylenetetrahydrofolate + glycine + H2O
-
 r

Synonyms

Synonyms Comment Organism
serine hydroxymethyltransferase
-
 Plasmodium falciparum
serine hydroxymethyltransferase
-
 Plasmodium berghei
serine hydroxymethyltransferase
-
 Plasmodium vivax
SHMT
-
 Plasmodium falciparum
SHMT
-
 Plasmodium berghei
SHMT
-
 Plasmodium vivax

Cofactor

Cofactor Comment Organism Structure
pyridoxal 5'-phosphate
-
 Plasmodium falciparum
pyridoxal 5'-phosphate
-
 Plasmodium berghei
pyridoxal 5'-phosphate
-
 Plasmodium vivax

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.000009
-
 at pH 7.0, temperature not specified in the publication Plasmodium berghei (+/-)-methyl 5-[3-(6-amino-5-cyano-4-isopropyl-3-methyl-1,4-dihydropyrano[2,3-c]pyrazol-4-yl)-5-cyanophenyl]thiophene-2-carboxylate
0.00006
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum methyl 5-[3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
0.00017
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum benzyl 5-[3-[(4S)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
0.00021
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum 6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
0.00021
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum methyl 3'-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5'-chloro[1,1'-biphenyl]-4-carboxylate
0.00022
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum 3'-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5'-cyano[1,1'-biphenyl]-3-carboxylic acid
0.00027
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum 5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]-N,N-dimethylthiophene-2-carboxamide
0.00029
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum 6-amino-4-(3,5-dichlorophenyl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
0.00037
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum (4R)-6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
0.00037
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum methyl 5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
0.00042
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum benzyl 5-[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate
0.00047
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum (4S)-6-amino-4-(5-cyano-3'-fluoro[1,1'-biphenyl]-3-yl)-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
0.00048
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum 6-amino-3-methyl-4-[3-(morpholin-4-yl)-5-(trifluoromethyl)phenyl]-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
0.00056
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum ethyl 4-[[3-[6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl](methyl)amino]butanoate
0.00542
-
 at pH 7.0, temperature not specified in the publication Plasmodium falciparum methyl 5-[3-[(4R)-6-amino-5-cyano-3-methyl-4-(propan-2-yl)-2,4-dihydropyrano[2,3-c]pyrazol-4-yl]-5-cyanophenyl]thiophene-2-carboxylate