Institute of Genomics and Systems Biology and The College

Lake of the Woods, IL, United States

Institute of Genomics and Systems Biology and The College

Lake of the Woods, IL, United States
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Stec J.,University of Illinois at Chicago | Stec J.,Chicago State University | Fomovska A.,Institute of Genomics and Systems Biology and The College | Fomovska A.,Mount Sinai School of Medicine | And 14 more authors.
ChemMedChem | Year: 2013

Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was used to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4′ of the well-known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16a and 16c have IC50 values of 250nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26nM, respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130nM in the enzyme-based assay. With respect to their excellent invitro activity as well as improved drug-like properties, the lead compounds 16a and 16c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Institute of Genomics and Systems Biology and The College
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2012

Toxoplasma gondii (T. gondii) is an apicomplexan parasite that can cause eye disease, brain disease, and death, especially in congenitally infected and immune-compromised people. Novel medicines effective against both active and latent forms of the parasite are greatly needed. The current study focused on the discovery of such medicines by exploring a family of potential inhibitors whose antiapicomplexan activity has not been previously reported. Initial screening efforts revealed that niclosamide, a drug approved for anthelmintic use, possessed promising activity in vitro against T. gondii. This observation inspired the evaluation of the activity of a series of salicylanilides and derivatives. Several inhibitors with activities in the nanomolar range with no appreciable in vitro toxicity to human cells were identified. An initial structure-activity relationship was explored. Four compounds were selected for evaluation in an in vivo model of infection, and two derivatives with potentially enhanced pharmacological parameters demonstrated the best activity profiles.

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