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Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues.
J Med Chem. 2004 Jun 17; 47(13):3427-37.JM

Abstract

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.

Authors+Show Affiliations

Welsh School of Pharmacy, Redwood Building, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15189039

Citation

Dardonville, Christophe, et al. "Selective Inhibition of Trypanosoma Brucei 6-phosphogluconate Dehydrogenase By High-energy Intermediate and Transition-state Analogues." Journal of Medicinal Chemistry, vol. 47, no. 13, 2004, pp. 3427-37.
Dardonville C, Rinaldi E, Barrett MP, et al. Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues. J Med Chem. 2004;47(13):3427-37.
Dardonville, C., Rinaldi, E., Barrett, M. P., Brun, R., Gilbert, I. H., & Hanau, S. (2004). Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues. Journal of Medicinal Chemistry, 47(13), 3427-37.
Dardonville C, et al. Selective Inhibition of Trypanosoma Brucei 6-phosphogluconate Dehydrogenase By High-energy Intermediate and Transition-state Analogues. J Med Chem. 2004 Jun 17;47(13):3427-37. PubMed PMID: 15189039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues. AU - Dardonville,Christophe, AU - Rinaldi,Eliana, AU - Barrett,Michael P, AU - Brun,Reto, AU - Gilbert,Ian H, AU - Hanau,Stefania, PY - 2004/6/11/pubmed PY - 2004/7/10/medline PY - 2004/6/11/entrez SP - 3427 EP - 37 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 47 IS - 13 N2 - 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. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/15189039/Selective_inhibition_of_Trypanosoma_brucei_6_phosphogluconate_dehydrogenase_by_high_energy_intermediate_and_transition_state_analogues_ L2 - https://dx.doi.org/10.1021/jm031066i DB - PRIME DP - Unbound Medicine ER -