Fig. 1. Selected benzoxaboroles are active against T. cruzi in vitro and in vivo.
a, Structure of key compounds evaluated, including the ultimate clinical candidate, AN15368. b, C57BL/6J mice received a single oral dose of AN14353 at the indicated concentration at 2 dpi with 2.5 × 105 tdTomato-expressing T. cruzi infection in the footpads. The relative increase in the fluorescent intensity of the footpads between 2 and 4 dpi was assessed by in vivo imaging (untreated: n = 8; AN15368: n = 10 individual feet). Asterisks represent the statistical significance of the difference between each treated group and the untreated control. c, C57BL/6J mice infected in the footpads with 2.5 × 105 luciferase-expressing parasites received a single oral dose of AN14353 (25 mg kg−1) or no treatment at 3 dpi and the bioluminescence signal of the feet was measured over 72 h (untreated: n = 2; AN15368: n = 6 individual feet). d, Daily oral treatment with AN14353 at 10 or 25 mg kg−1 was administered for 40 consecutive days to C57BL/6J mice starting at 15 d post intraperitoneal infection with 104 T. cruzi trypomastigotes. Parasite load in skeletal muscle was determined by qPCR following cyclophosphamide-induced immunosuppression (untreated and treated groups: n = 4 mice; naïve n = 1). e, IFN-gamma deficient mice intraperitoneally infected with T. cruzi received a daily oral treatment with AN14353 (25 mg kg−1) for 40 d (AN15368: n = 4; untreated: n = 9 mice; naïve n = 3). Parasite load in skeletal muscle after immunosuppression with cyclophosphamide was assessed by qPCR. Untreated animals in e were killed and tissue samples collected before the end of the experiment due to the high susceptibility to T. cruzi infection and the lethal pathology developed by IFN-gamma-deficient animals. Red filled symbols denote animals in which parasites were detected by fresh blood smears or haemoculture. Dotted lines represent the cut-off in the qPCR assays. Data are presented as mean ± s.e.m. For b, d and e: Mann-Whitney test, two tailed; for c: unpaired t-test, 95% confidence interval. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.