by Thompson AM, O’Connor PD, Marshall AJ, Francisco AF, Kelly JM, Riley J, Read KD, Perez CJ, Cornwall S, Thompson RCA, Keenan M, White KL, Charman SA, Zulfiqar B, Sykes ML, Avery VM, Chatelain E, Denny WA. European Journal of Medicinal Chemistry 2020; 207:112849. doi: 10.1016/j.ejmech.2020.112849
Summary: A 900-compound library of nitroimidazole derivatives related to pretomanid, a treatment for highly challenging cases of tuberculosis, was screened against the causative agent of Chagas disease, Trypanosoma cruzi. Several structurally diverse hits with an unknown mode of action were identified. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies laid the foundation for a more in-depth assessment of the best leads. Comparative appraisal of one preferred lead in a chronic infection mouse model provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.