Abstract
The synthesis and biological evaluation of three series of 6-phosphogluconate (6PG) analogues is described. (2R)-2-Methyl-4,5-dideoxy, (2R)-2-methyl-4-deoxy and 2,4-dideoxy analogues of 6PG were tested as inhibitors of 6-phosphogluconate dehydrogenase (6PGDH) from sheep liver and also Trypanosoma brucei where the enzyme is a validated drug target. Among the three series of analogues, seven compounds were found to competitively inhibit 6PGDH from T. brucei and sheep liver enzymes at micromolar concentrations. Six inhibitors belong to the (2R)-2-methyl-4-deoxy series (6, 8, 10, 12, 21, 24) and one is a (2R)-2-methyl-4,5-dideoxy analogue (29b). The 2,4-dideoxy analogues of 6PG did not inhibit both enzymes. The trypanocidal effect of the compounds was also evaluated in vitro against T. brucei rhodesiense as well as other related trypanosomatid parasites (i.e., Trypanosoma cruzi and Leishmania donovani).
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Deoxy Sugars / chemistry
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Gluconates / chemical synthesis*
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Gluconates / chemistry
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Gluconates / pharmacology
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Leishmania donovani / drug effects
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Liver / enzymology
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Phosphogluconate Dehydrogenase / antagonists & inhibitors*
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Phosphogluconate Dehydrogenase / metabolism
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Sheep
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Structure-Activity Relationship
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Trypanocidal Agents / chemical synthesis*
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Trypanocidal Agents / pharmacology
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Trypanosoma brucei brucei / drug effects
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Trypanosoma brucei brucei / enzymology
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Trypanosoma cruzi / drug effects
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Trypanosoma cruzi / enzymology
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Trypanosomiasis, African / drug therapy
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Trypanosomiasis, African / veterinary*
Substances
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Deoxy Sugars
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Enzyme Inhibitors
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Gluconates
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Trypanocidal Agents
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Phosphogluconate Dehydrogenase
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6-phosphogluconic acid