Figure 1.
Praziquantel (PZQ), mefloquine (MFQ), artemether (ARTM), and trioxaquines PA1259 and PA1647.
Figure 2.
Comparative In vitro activities.
PA1259 (▪), praziquantel (★), artemether (⧫), and mefloquine (•) on cercariae (A), on 21-days old schistosomules (B) and on 49-days old adult (C) S. mansoni. Cultured larvae (cercariae or schistosomules) or adults were treated with compounds at 5 µg/ml or 50 µg/ml, respectively.
Table 1.
In vivo effect of PA1259 and praziquantel.
Table 2.
In vivo effect of PA1647 combined with praziquantel on 21-day-old schistosomula.
Figure 3.
Optic microscopy of treated worms.
S. mansoni females treated with PA1259 at 50 µg/mL (A, C, and E), compared to control worms (B and D). Hz stands for hemozoin. In B and D: black Hz in a well defined gut; in C: Few minutes after treatment, Hz turns to brown inside the gut; in E) one hour after treatment the brown pigment was transfered outside of the gut.
Figure 4.
SEM images of the mid-body region of S. mansoni adult females.
Control worms (a), compared to worms treated with b) praziquantel (PZQ), c) trioxaquine PA1259, d) mefloquine (MFQ), or e) artemether (ARTM). Magnification ×1000 (a1-e1), ×2000 (a2-e2), ×5000 (a3-e3); the bars stand for 10 µm.
Figure 5.
(a) TEM image of hemozoin pellets of untreated S. mansoni female. (b) Element analysis of 3 differents part of the picture (a): b1. Background: low contrasted zone, b2. Hemozoin pellets in early stage formation, b3. Hemozoin pellets at final stage.
Figure 6.
TEM images of hemozoin (Hz) inside the gut.
Control worms (a), compared to worms treated with b) mefloquine (MFQ), c) praziquantel (PZQ) or d, e, f) trioxaquine PA1259, and g) artemether. The scale bars stand for 2 µm in panels a, b, c, d, f, and g, and for 5 µm in panel e.
Figure 7.
Control worms (a), compared to worms treated with b) praziquantel (PZQ), c) trioxaquine PA1259, d) mefloquine (MFQ), or e) artemether (ARTM). The scale bars stand for 2 µm in panels a1-e1, and for 1 µm in panels a2-e2.
Figure 8.
Reduced or radicals oxygen species dosage.
A. Superoxide anion (O2•−) was dosed using Nitro Blue Tetrazolium method B. Hydrogen peroxide (H2O2) was dosed using Amplex Red method. B. Nitric Oxide (NO•) was dosed using DAF-2 method.
Figure 9.
LC-MS analysis of the extract of Schistosoma mansoni treated with artemether (50 µg/mL).
Extracted ionic current (EIC) traces for: (a) m/z = 616.2 (Heme, M+); (b) m/z = 936.4 (“Complete” heme-artemether adduct 1, (M-H+Na)+; (c) m/z = 854.4 (heme-artemether adduct 2, MH+). (Inserts correspond to the mass spectra of circled chromatographic peaks).
Figure 10.
LC-MS analysis of the extract of Schistosoma mansoni treated with trioxaquine PA1259 (50 µg/mL).
Extracted ionic current (EIC) traces for: (a) m/z = 616.2 (Heme, M+); (b) m/z = 551.3 (“Complete” heme-PA1259 adducts 3 and/or 4, MH+/2); (c) m/z = 730.3 (heme-PA1259 adduct 5, MH+). (Inserts correspond to the mass spectra of chromatographic peaks with arrows).
Table 3.
Relative intensity of damages on cultured S. mansoni, observed by electron microscopy.
Figure 11.
Mechanism of alkylation of heme by artemether (the oval stands for the protoporphyrin-IX ligand).
Figure 12.
Mechanism of alkylation of heme by trioxaquine PA1259 (the oval stands for the protoporphyrin-IX ligand).
Figure 13.
Oxidative cleavage of heme to fragment with m/z = 347.2 (M+).