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Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis.
Bioorg Med Chem. 2003 Jul 17; 11(14):3205-14.BM

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+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

12818683

Citation

Dardonville, Christophe, et al. "Synthesis and Biological Evaluation of Substrate-based Inhibitors of 6-phosphogluconate Dehydrogenase as Potential Drugs Against African Trypanosomiasis." Bioorganic & Medicinal Chemistry, vol. 11, no. 14, 2003, pp. 3205-14.
Dardonville C, Rinaldi E, Hanau S, et al. Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis. Bioorg Med Chem. 2003;11(14):3205-14.
Dardonville, C., Rinaldi, E., Hanau, S., Barrett, M. P., Brun, R., & Gilbert, I. H. (2003). Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis. Bioorganic & Medicinal Chemistry, 11(14), 3205-14.
Dardonville C, et al. Synthesis and Biological Evaluation of Substrate-based Inhibitors of 6-phosphogluconate Dehydrogenase as Potential Drugs Against African Trypanosomiasis. Bioorg Med Chem. 2003 Jul 17;11(14):3205-14. PubMed PMID: 12818683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis. AU - Dardonville,Christophe, AU - Rinaldi,Eliana, AU - Hanau,Stefania, AU - Barrett,Michael P, AU - Brun,Reto, AU - Gilbert,Ian H, PY - 2003/6/24/pubmed PY - 2004/2/28/medline PY - 2003/6/24/entrez SP - 3205 EP - 14 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 11 IS - 14 N2 - 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). SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/12818683/Synthesis_and_biological_evaluation_of_substrate_based_inhibitors_of_6_phosphogluconate_dehydrogenase_as_potential_drugs_against_African_trypanosomiasis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968089603001913 DB - PRIME DP - Unbound Medicine ER -