Toxoplasma gondii infections cause suffering and mortality in those congenitally infected or immune compromised. Easily genetically manipulated and disseminated in nature, this parasite is considered a category B bioterrorism pathogen. Improved, new antimicrobials are greatly needed to treat this infection. Type 2 fatty acid biosynthesis (fas), structurally different from mammalian type 2 fas, is a validated target essential for Toxoplasma gondii growth in vitro and survival of the parasite in mice. Enoyl reductase (ENR) is an enzyme in the type 2 fas biosynthetic pathway. Triclosan and two newly synthesized lead compounds, in nanomolar amounts, inhibit T. gondii ENR activity and in low micromolar amounts inhibit T. gondii growth in vitro. Triclosan also inhibits T. gondii growth in mice. Structures of T. gondii ENR complexed with inhibitors have been solved. Unique features of T. gondii ENR will be used to develop novel tight binding inhibitors. With these data in hand, and to be acquired during the work proposed, using a structure based design approach, it will be possible to modify and thereby optimize and create a novel tight binding inhibitor of T. gondii ENR. We will create a new compound based on theoretical information derived from analyses of lead inhibitory compounds'and ENR structures and their interactions coupled with enzyme and parasite inhibitory data. Information we have in hand from our preliminary analyses of triclosan and other novel compounds we have synthesized and tested in enzyme, in vitro parasite and co-crystallization and structure analyses will inform this structure-based ENR inhibitor design program. If new leads are needed, as an additional alternative approach, a Catalyst-based pharmacophore approach will be used. Inhibitors will undergo rounds of modification and testing to find more druggable ENR inhibitors with better ADMET profiles. As new inhibitory compounds are identified, their fit to the enzyme binding site will be compared, and hybrid structures that incorporate desirable features from different molecular scaffolds will be created to optimize activity. ClogP, or PSA, and Caco2 cell permeability will be optimized. It is likely that either a completely new molecule will be created or that the phenyl rings of triclosan will be converted to heterocycles having improved solubility, activity, and safety.
Development of inhibitors useful as medicines will be progressed by modification of lead compounds to obviate potential problems with resistance and toxicity and optimize solubility, pharmokinetics, and bioavailability. This work will create a greatly needed novel class of compound to treat toxoplasmosis.
|Zhou, Ying; Fomovska, Alina; Muench, Stephen et al. (2014) Spiroindolone that inhibits PfATPase4 is a potent, cidal inhibitor of Toxoplasma gondii tachyzoites in vitro and in vivo. Antimicrob Agents Chemother 58:1789-92|
|Wilkinson, Craig; McPhillie, Martin J; Zhou, Ying et al. (2014) The benzimidazole based drugs show good activity against T. gondii but poor activity against its proposed enoyl reductase enzyme target. Bioorg Med Chem Lett 24:911-6|
|Stec, Jozef; Fomovska, Alina; Afanador, Gustavo A et al. (2013) Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii. ChemMedChem 8:1138-60|
|Schrader, Florian C; Glinca, Serghei; Sattler, Julia M et al. (2013) Novel type II fatty acid biosynthesis (FAS II) inhibitors as multistage antimalarial agents. ChemMedChem 8:442-61|
|Muench, Stephen P; Stec, Jozef; Zhou, Ying et al. (2013) Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides. Bioorg Med Chem Lett 23:3551-5|
|Cheng, Gang; Muench, Stephen P; Zhou, Ying et al. (2013) Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase. Bioorg Med Chem Lett 23:2035-43|
|Stec, Jozef; Huang, Qingqing; Pieroni, Marco et al. (2012) Synthesis, biological evaluation, and structure-activity relationships of N-benzoyl-2-hydroxybenzamides as agents active against P. falciparum (K1 strain), Trypanosomes, and Leishmania. J Med Chem 55:3088-100|
|Fomovska, Alina; Huang, Qingqing; El Bissati, Kamal et al. (2012) Novel N-benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway. Antimicrob Agents Chemother 56:2666-82|
|Hutson, Samuel L; Mui, Ernest; Kinsley, Karen et al. (2010) T. gondii RP promoters & knockdown reveal molecular pathways associated with proliferation and cell-cycle arrest. PLoS One 5:e14057|
|Tipparaju, Suresh K; Muench, Stephen P; Mui, Ernest J et al. (2010) Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. J Med Chem 53:6287-300|