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Stephen P Muench,
Jozef Stec,
Ying Zhou,
Gustavo A Afanador,
Martin J McPhillie,
Mark R Hickman, Patty J Lee,
Susan E Leed,
Jennifer M Auschwitz,
Sean T Prigge,
David W Rice,
Rima McLeod
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ABSTRACT: The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery.
Bioorganic & medicinal chemistry letters 04/2013; · 2.65 Impact Factor
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Gang Cheng,
Stephen P Muench,
Ying Zhou,
Gustavo A Afanador,
Ernest J Mui,
Alina Fomovska,
Bo Shiun Lai,
Sean T Prigge,
Stuart Woods,
Craig W Roberts,
Mark R Hickman, Patty J Lee,
Susan E Leed,
Jennifer M Auschwitz,
David W Rice,
Rima McLeod
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ABSTRACT: Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.
Bioorganic & medicinal chemistry letters 02/2013; · 2.65 Impact Factor
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Alina Fomovska,
Qingqing Huang,
Kamal El Bissati,
Ernest J Mui,
William H Witola,
Gang Cheng,
Ying Zhou,
Caroline Sommerville,
Craig W Roberts,
Sam Bettis, [......],
Mark R Hickman, Patty J Lee,
Susan E Leed,
Jennifer M Auschwitz,
Marco Pieroni,
Jozef Stec,
Stephen P Muench,
David W Rice,
Alan P Kozikowski,
Rima McLeod
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ABSTRACT: Toxoplasma gondii is a protozoan parasite that can damage the human brain and eyes. There are no curative medicines. Herein, we describe our discovery of N-benzoyl-2-hydroxybenzamides as a class of compounds effective in the low nanomolar range against T. gondii in vitro and in vivo. Our lead compound, QQ-437, displays robust activity against the parasite and could be useful as a new scaffold for development of novel and improved inhibitors of T. gondii. Our genome-wide investigations reveal a specific mechanism of resistance to N-benzoyl-2-hydroxybenzamides mediated by adaptin-3β, a large protein from the secretory protein complex. N-Benzoyl-2-hydroxybenzamide-resistant clones have alterations of their secretory pathway, which traffics proteins to micronemes, rhoptries, dense granules, and acidocalcisomes/plant-like vacuole (PLVs). N-Benzoyl-2-hydroxybenzamide treatment also alters micronemes, rhoptries, the contents of dense granules, and, most markedly, acidocalcisomes/PLVs. Furthermore, QQ-437 is active against chloroquine-resistant Plasmodium falciparum. Our studies reveal a novel class of compounds that disrupts a unique secretory pathway of T. gondii, with the potential to be used as scaffolds in the search for improved compounds to treat the devastating diseases caused by apicomplexan parasites.
Antimicrobial Agents and Chemotherapy 02/2012; 56(5):2666-82. · 4.84 Impact Factor
