Antitrypanosomal lead discovery: Identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth.
J Med Chem. 2013 Feb 28;
Authors: Andriani G, Amata E, Beatty J, Clements Z, Coffey BJ, Courtemanche G, Devine W, Erath J, Juda CE, Wawrzak Z, Wood JT, Lepesheva GI, Rodriguez A, Pollastri MP
Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi, and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi while displaying a selectivity margin of over 160-fold. We report in vitro drug metabolism and properties profiling results and our elucidation of the mechanism of action of this chemotype, which acts via the T cruzi CYP51 enzyme. This is an essential parasite enzyme involved in sterol biosynthesis. We report X-ray crystallographic evidence of the binding of compound 4c to T. cruzi CYP51 and compare it to previously reported structural biology results of other inhibitors. This enzyme has been the target of other anti-trypanosomal agents in the past; however, due to the high potency and small molecular size in comparison to current azole-based T. cruzi CYP51 inhibitor chemotypes such as VNF, posaconazole, and ravuconazole, 4c displays a significantly better ligand efficiency and a shorter synthetic route, and should therefore be considered a promising chemotype for further optimization.
PMID: 23448316 [PubMed - as supplied by publisher]