Identification and Development of Novel Inhibitors ... - ACS Publications

Aug 10, 2010 - Fiona L. Henriquez,. 3. Alan P. Kozikowski,‡ David W. Rice,§ and. Rima L. McLeod*, ). ‡Drug Discovery Program, Department of Medic...
0 downloads 0 Views 1MB Size
NIH Public Access Author Manuscript J Med Chem. Author manuscript; available in PMC 2011 September 9.

NIH-PA Author Manuscript

Published in final edited form as: J Med Chem. 2010 September 9; 53(17): 6287–6300. doi:10.1021/jm9017724.

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†, and Rima L. McLeod#,* ‡ Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA †

Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, UK

#

NIH-PA Author Manuscript

Department of Ophthalmology and Visual Sciences, Pediatrics (Infectious Diseases), Committees on Genetics, Immunology and Molecular Medicine, Institute of Genomics and Systems Biology, and The College, The University of Chicago, Chicago, Illinois, USA ^

Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, UK

§

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA ∫

Department of Immunology and Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, UK

Abstract

NIH-PA Author Manuscript

Toxoplasmosis causes significant morbidity and mortality and yet available medicines are limited by toxicities and hypersensitivity. Since 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 anti-parasite MIC90s ≤6μM without toxicity to host cells, three compounds have IC90s