Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase

Suresh K Tipparaju, Stephen P Muench, Ernest J Mui, Sergey N Ruzheinikov, Jeffrey Z. Lu, Samuel L Hutson, Michael J. Kirisits, Sean T. Prigge, Craig Roberts, Fiona L Henriquez, Alan P Kozikowski, David W Rice, Rima L McLeod

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Abstract

Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s <or = 6 microM without toxicity to host cells, three compounds have IC(90)s <45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.
Original languageEnglish
Pages (from-to)6287-6300
Number of pages14
JournalJournal of Medicinal Chemistry
Volume53
Issue number17
Early online date10 Aug 2010
DOIs
Publication statusPublished - 2010

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Keywords

  • animals
  • cultured cells
  • coccidiostats
  • crystallography X-Ray
  • cytochrome P-450 enzyme system
  • enoyl-(acyl-carrier-protein) reductase (NADH)
  • fibroblasts
  • humans
  • mice
  • microbial sensitivity tests
  • liver microsomes
  • molecular models
  • molecular structure
  • nitriles
  • nitrobenzenes
  • phenyl ethers
  • pyridines
  • structure-activity relationship
  • toxoplasma
  • toxoplasmosis

Cite this

Tipparaju, S. K., Muench, S. P., Mui, E. J., Ruzheinikov, S. N., Lu, J. Z., Hutson, S. L., ... McLeod, R. L. (2010). Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. Journal of Medicinal Chemistry, 53(17), 6287-6300. https://doi.org/10.1021/jm9017724