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Literature summary extracted from

  • Spry, C.; Sewell, A.L.; Hering, Y.; Villa, M.V.J.; Weber, J.; Hobson, S.J.; Harnor, S.J.; Gul, S.; Marquez, R.; Saliba, K.J.
    Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation (2018), Eur. J. Med. Chem., 143, 1139-1147 .
    View publication on PubMed

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.7.1.33 (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611. CJ-15,801 is phosphorylated by pantothenate kinase (PanK). Subsequently, phospho-CJ-15,801 is accepted as a substrate by the next enzyme in the pathway (phosphopantothenoylcysteine synthetase, PPCS), and reacts to become cytidylylated. The cytidylylated phospho-CJ-15,801, which closely mimics the natural reaction intermediate and binds tightly and reversibly to the enzyme, does not react further and instead inhibits the enzyme Plasmodium falciparum
2.7.1.33 (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid
-
 Plasmodium falciparum
2.7.1.33 (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid
-
 Plasmodium falciparum
2.7.1.33 (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid
-
 Plasmodium falciparum
2.7.1.33 benzyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 benzyl (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 benzyl (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 benzyl (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-2-methyl-3-[[(4R)-2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-(2-oxoazepan-1-yl)prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-(2-oxoazocan-1-yl)prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-(2-oxoazonan-1-yl)prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-benzamido-2-methylprop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-benzamidoprop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-[(pyridine-3-carbonyl)amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]-2-methylprop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2E)-3-[[(4R)-2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 ethyl (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 methyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 methyl (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 methyl (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 methyl (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 additional information structure-activity analysis of (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid (CJ-15,801) analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation. Inhibitor selectivity, overview. The enamide analogues of pantothenate may inhibit pantothenate phosphorylation by one of two mechanisms: (i) by directly inhibiting PfPanK, or (ii) by serving as alternate substrates that are competitively phosphorylated. It is noteworthy that the IC50 value of the best pantothenate phosphorylation inhibitor is 13fold lower than the pantothenate concentration present in the assay (0.0018 mM). Assuming competition for the same binding site, this is consistent with the enamide binding PanK with higher affinity and/or being turned over more slowly than the natural substrate. Effect of pantothenate supplementation on the antiplasmodial activity of CJ-15,801 and derivatives Plasmodium falciparum
2.7.1.33 tert-butyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 tert-butyl (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 tert-butyl (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum
2.7.1.33 tert-butyl (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
-
 Plasmodium falciparum

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.7.1.33 Mg2+ required Plasmodium falciparum

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.1.33 ATP + (R)-pantothenate Plasmodium falciparum
-
 ADP + (R)-4'-phosphopantothenate
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.7.1.33 Plasmodium falciparum Q8ILP4
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.1.33 ATP + (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid CJ-15,801, the compound is phosphorylated by pantothenate kinase (PanK). Subsequently, phospho-CJ-15,801 is accepted as a substrate by the next enzyme in the pathway (phosphopantothenoylcysteine synthetase, PPCS), and reacts to become cytidylylated. The cytidylylated phospho-CJ-15,801, which closely mimics the natural reaction intermediate and binds tightly and reversibly to the enzyme, does not react further and instead inhibits the enzyme Plasmodium falciparum ADP + 4'-phospho-CJ-15,801
-
 ?
2.7.1.33 ATP + (R)-pantothenate
-
 Plasmodium falciparum ADP + (R)-4'-phosphopantothenate
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.7.1.33 PanK
-
 Plasmodium falciparum

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
2.7.1.33 0.013
-
 pH and temperature not specified in the publication Plasmodium falciparum benzyl (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.036
-
 pH and temperature not specified in the publication Plasmodium falciparum (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid
2.7.1.33 0.039
-
 pH and temperature not specified in the publication Plasmodium falciparum tert-butyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.042
-
 pH and temperature not specified in the publication Plasmodium falciparum tert-butyl (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.061
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-(2-oxoazonan-1-yl)prop-2-enoate
2.7.1.33 0.089
-
 pH and temperature not specified in the publication Plasmodium falciparum benzyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.093
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-2-methyl-3-[[(4R)-2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl]amino]prop-2-enoate
2.7.1.33 0.093
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-(2-oxoazocan-1-yl)prop-2-enoate
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum benzyl (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum benzyl (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum ethyl (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum methyl (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum methyl (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum tert-butyl (2E)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.1
-
 above, pH and temperature not specified in the publication Plasmodium falciparum tert-butyl (2Z)-3-[[(2S)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.12
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-benzamido-2-methylprop-2-enoate
2.7.1.33 0.144
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-[[(4R)-2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl]amino]prop-2-enoate
2.7.1.33 0.158
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-benzamidoprop-2-enoate
2.7.1.33 0.159
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.159
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.181
-
 pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-(2-oxoazepan-1-yl)prop-2-enoate
2.7.1.33 0.2
-
 above, pH and temperature not specified in the publication Plasmodium falciparum (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid
2.7.1.33 0.2
-
 above, pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-[(pyridine-3-carbonyl)amino]prop-2-enoate
2.7.1.33 0.2
-
 above, pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]-2-methylprop-2-enoate
2.7.1.33 0.2
-
 above, pH and temperature not specified in the publication Plasmodium falciparum ethyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.2
-
 above, pH and temperature not specified in the publication Plasmodium falciparum methyl (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate
2.7.1.33 0.2
-
 above, pH and temperature not specified in the publication Plasmodium falciparum methyl (2Z)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoate

General Information

EC Number General Information Comment Organism
2.7.1.33 malfunction structure-activity analysis of (2E)-3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]prop-2-enoic acid (CJ-15,801) analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation. The conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. The antiplasmodial potency of CJ-15,801 analogues, that retain the R-pantoyl and trans-substituted enamide moieties, correlates with inhibition of Plasmodium falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation Plasmodium falciparum