1. AntitrypanosomalLead Discovery: Identification ofa Ligand-Efficient Inhibitor of Trypanosoma cruziCYP51 and Parasite Growth.
- Author
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Andriani, Grasiella, Amata, Emanuele, Beatty, Joel, Clements, Zeke, Coffey, Brian J., Courtemanche, Gilles, Devine, William, Erath, Jessey, Juda, Cristin E., Wawrzak, Zdzislaw, Wood, JodiAnne T., Lepesheva, Galina I., Rodriguez, Ana, and Pollastri, Michael P.
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LIGANDS (Biochemistry) , *TRYPANOSOMA cruzi , *CHAGAS' disease , *MICROBIAL growth , *STRUCTURE-activity relationship in pharmacology , *DRUG metabolism - Abstract
Chagasdisease is caused by the intracellular protozoan parasite Trypanosomal cruzi, and current drugs are lackingin terms of desired safety and efficacy profiles. Following on a recentlyreported high-throughput screening campaign, we have explored initialstructure–activity relationships around a class of imidazole-basedcompounds. This profiling has uncovered compounds 4c(NEU321)and 4j(NEU704), which are potent against in vitro culturesof T. cruziand are greater than 160-foldselective over host cells. We report in vitro drug metabolism andproperties profiling of 4cand show that this chemotypeinhibits the T. cruziCYP51 enzyme,an observation confirmed by X-ray crystallographic analysis. We comparethe binding orientation of 4cto that of other, previouslyreported inhibitors. We show that 4cdisplays a significantlybetter ligand efficiency and a shorter synthetic route over previouslydisclosed CYP51 inhibitors, and should therefore be considered a promisinglead compound for further optimization. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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