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 W Roberts, Fiona L Henriquez, Alan P Kozikowski, David W. Rice, Rima L McLeod

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43 Citations (Scopus)


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)6287-300
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number17
Publication statusPublished - 9 Sep 2010
Externally publishedYes


  • Animals
  • Cells, Cultured
  • Coccidiostats
  • Crystallography, X-Ray
  • Cytochrome P-450 Enzyme Inhibitors
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
  • Fibroblasts
  • Humans
  • In Vitro Techniques
  • Mice
  • Microbial Sensitivity Tests
  • Microsomes, Liver
  • Models, Molecular
  • Molecular Structure
  • Nitriles
  • Nitrobenzenes
  • Phenyl Ethers
  • Pyridines
  • Structure-Activity Relationship
  • Toxoplasma
  • Toxoplasmosis


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