Selective Inhibition of Trypanosoma brucei 6-Phosphogluconate Dehydrogenase by High-Energy Intermediate and Transition-State Analogues

• Published in: Journal of medicinal chemistry Vol. 47; no. 13; pp. 3427 - 3437
• Main Authors: Dardonville, Christophe, Rinaldi, Eliana, Barrett, Michael P, Brun, Reto, Gilbert, Ian H, Hanau, Stefania
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.06.2004; Amer Chemical Soc
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Butyrates - chemical synthesis; Butyrates - chemistry; Butyrates - pharmacology; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gluconates - chemistry; Gluconates - metabolism; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Life Sciences & Biomedicine; Liver - enzymology; Medical sciences; Oxidation-Reduction; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphogluconate Dehydrogenase - antagonists & inhibitors; Phosphogluconate Dehydrogenase - chemistry; Science & Technology; Sheep; Structure-Activity Relationship; Sulfoxides - chemical synthesis; Sulfoxides - chemistry; Sulfoxides - pharmacology; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - enzymology; COMPETITIVE INHIBITORS; PHOSPHOGLUCOSE ISOMERASE; ENZYME; MECHANISM; ACIDS; DERIVATIVES; Kinetoplastida; Protozoa; Enzyme; Phosphogluconate 2-dehydrogenase; Hydroxysulfoxide; Hydroxamic acid; Enzyme inhibitor; Selectivity; In vitro; Phosphorus Organic compounds; Antiprotozoal agent; Structure activity relation; Carboxylic acid; Transition state; Organic phosphate; Sulfoxide; Parasiticide; Oxidoreductases; Chemical synthesis; Trypanosoma brucei
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm031066i

Two series of compounds were designed to mimic the transition state and high-energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate dehydrogenase (6PGDH). Sulfoxide analogues (7−11) were designed to mimic the transition state during the oxidation of the substrate to 3-keto-6-phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and amide derivatives of d-erythronic acid were designed to mimic the 1,2-cis-enediol HEI of the 6PGDH reaction. These two series of compounds were assayed as competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T. brucei 6PGDH with a K i in the nanomolar range.