Fig. 2. In vitro activity of DSM265 and its analogs on DHODH and P

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Fig. 2. In vitro activity of DSM265 and its analogs on DHODH and P Fig. 2. In vitro activity of DSM265 and its analogs on DHODH and P. falciparum parasites. In vitro activity of DSM265 and its analogs on DHODH and P. falciparum parasites. (A) DHODH inhibition. IC50 values are reported in Table 1. Error bars show SEM for three technical replicates per concentration. Each fitted IC50 was obtained from 30 to 33 data points per fit. (B) In vitro P. falciparum 3D7 growth inhibition. Fitted EC50s were 0.0018 μg/ml (0.0011 to 0.0028), 0.079 μg/ml (0.042 to 0.15), and 0.00020 μg/ml (0.00011 to 0.00056) for DSM265, DSM450, and DSM430, respectively, with the 95% confidence intervals in parenthesis (three technical replicates per concentration and 18 to 24 data points per fit; the plot shows mean ± SEM). (C) Effects on P. falciparum 3D7 blood-stage phenotype and development. Cells were treated with drug at 10 × EC50, and parasites were evaluated by microscopy 48 hours after drug addition (minimally 200 cells were counted per condition). Atovaquone (Ato), artemisinin (Art), and pyrimethamine (Pyr) were used as controls. Images of representative parasites from the counted stages are displayed (R, rings; YT, young trophozoite; MT, mature trophozoite; S, schizont; P, pyknotic). (D) In vitro killing curves for treatment of P. falciparum 3D7 blood-stage parasites. Data for 10 × EC50 and 100 × EC50 (where EC50 = 0.0046 μg/ml) (four technical replicates showing the mean and SD) are displayed for DSM265. Data for artemisinin, atovaquone, pyrimethamine, and chloroquine (Chl) were previously reported (33). (E) Comparative DSM265 kill rates calculated from (D). PRR (parasite reduction ratio), the log number of parasites killed per asexual life cycle (48 hours); Lag phase, time before parasite killing begins; PCT (parasite clearance time), time to achieve 99.9% parasite kill. Primary data are provided in table S19. Margaret A. Phillips et al., Sci Transl Med 2015;7:296ra111 Copyright © 2015, American Association for the Advancement of Science