title: Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis.
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).
authors.affiliation: Welsh School of Pharmacy, Redwood building, Cardiff University, King Edward VII Avenue, CF10 3XF, Cardiff, UK.
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardonville
authors.forename: Eliana
authors.initials: E
authors.lastname: Rinaldi
authors.forename: Stefania
authors.initials: S
authors.lastname: Hanau
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D003837:Deoxy Sugars / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005942:Gluconates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D008099:Liver / Q000201:enzymology; D010734:Phosphogluconate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000662:veterinary*
chemical_list: D003837:Deoxy Sugars; D004791:Enzyme Inhibitors; D005942:Gluconates; D014344:Trypanocidal Agents; D010734:Phosphogluconate Dehydrogenase; C008884:6-phosphogluconic acid