Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues.
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 Ki in the nanomolar range.
Dardonville
Christophe
C
Welsh School of Pharmacy, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom.
Rinaldi
Eliana
E
Barrett
Michael P
MP
Brun
Reto
R
Gilbert
Ian H
IH
Hanau
Stefania
S
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005942:Gluconates / Q000737:chemistry / Q000378:metabolism; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D010734:Phosphogluconate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012756:Sheep; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
C487573:3-keto-6-phosphogluconic acid; D000577:Amides; D000962:Antimalarials; D002087:Butyrates; D004791:Enzyme Inhibitors; D005942:Gluconates; D006877:Hydroxamic Acids; D013454:Sulfoxides; D014344:Trypanocidal Agents; C121691:erythronic acid; D010734:Phosphogluconate Dehydrogenase