TY - JOUR
T1 - In vitro and in vivo activity of 3-alkoxy-1,2-dioxolanes against Schistosoma mansoni
AU - Ingram, Katrin
AU - Schiaffo, Charles E.
AU - Sittiwong, Wantanee
AU - Benner, Evan
AU - Dussault, Patrick H.
AU - Keiser, Jennifer
N1 - Funding Information:
This work was supported by the Swiss National Science Foundation (project no. PPOOA3_114941 and PPOOP3_135170 to J. K.), the Scientific & Technological Cooperation Programme Switzerland-Russia, the Medicines for Malaria Venture (P. H. D. and C. E. S.), the Nebraska Research Initiative (P. H. D.) and the University of Nebraska-Lincoln (W. S. and E. B.). Parts of this research were conducted in facilities remodelled with National Institutes of Health support (RR016544).
PY - 2012/8
Y1 - 2012/8
N2 - Objectives: Compounds characterized by a peroxidic skeleton are an interesting starting point for antischistosomal drug discovery. Previously a series of 3-alkoxy-1,2-dioxolanes, which are chemically stable cyclic peroxides, demonstrated significant in vitro activity against Plasmodium falciparum. We aimed to evaluate the potential of these compounds against Schistosoma mansoni and elucidate the roles of iron and peroxidic groups in activity. Methods: Drugs were tested against juvenile and adult stages of S. mansoni in vitro and in vivo. Selected structures were assessed in vitro against schistosomes in the presence of additional iron sources. In addition, drugs were tested in vitro and in vivo against Echinostoma caproni, a non-blood-feeding intestinal fluke. Finally, the activity of non-peroxidic analogues was evaluated. Results: Three dioxolanes displayed IC 50s ≤20.1 μM against adult schistosomes and values as low as 4.2 μM against newly transformed schistosomula. Nonetheless, only moderate, non-significant worm burden reductions were observed after treatment of mice harbouring adult infections. Drugs lacked activity against juvenile schistosomes in vivo. Two selected dioxolanes showed in vitro activity against E. caproni down to concentrations of 5 mg/L, but none of the compounds revealed in vivo activity. All tested non-peroxidic analogues lacked activity in vitro against both parasites. Conclusions: Selected dioxolanes presented interesting in vitro activity, but low in vivo activities have to be overcome to identify a lead candidate. Although the inactivity of non-peroxidic analogues underlines the necessity of a peroxide functional group, incubation of adult schistosomes with additional iron sources did not alter activity, supporting an iron-independent mode of activation.
AB - Objectives: Compounds characterized by a peroxidic skeleton are an interesting starting point for antischistosomal drug discovery. Previously a series of 3-alkoxy-1,2-dioxolanes, which are chemically stable cyclic peroxides, demonstrated significant in vitro activity against Plasmodium falciparum. We aimed to evaluate the potential of these compounds against Schistosoma mansoni and elucidate the roles of iron and peroxidic groups in activity. Methods: Drugs were tested against juvenile and adult stages of S. mansoni in vitro and in vivo. Selected structures were assessed in vitro against schistosomes in the presence of additional iron sources. In addition, drugs were tested in vitro and in vivo against Echinostoma caproni, a non-blood-feeding intestinal fluke. Finally, the activity of non-peroxidic analogues was evaluated. Results: Three dioxolanes displayed IC 50s ≤20.1 μM against adult schistosomes and values as low as 4.2 μM against newly transformed schistosomula. Nonetheless, only moderate, non-significant worm burden reductions were observed after treatment of mice harbouring adult infections. Drugs lacked activity against juvenile schistosomes in vivo. Two selected dioxolanes showed in vitro activity against E. caproni down to concentrations of 5 mg/L, but none of the compounds revealed in vivo activity. All tested non-peroxidic analogues lacked activity in vitro against both parasites. Conclusions: Selected dioxolanes presented interesting in vitro activity, but low in vivo activities have to be overcome to identify a lead candidate. Although the inactivity of non-peroxidic analogues underlines the necessity of a peroxide functional group, incubation of adult schistosomes with additional iron sources did not alter activity, supporting an iron-independent mode of activation.
KW - Chemotherapy
KW - Non-peroxidic analogues
KW - Peroxides
KW - Schistosomiasis
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U2 - 10.1093/jac/dks141
DO - 10.1093/jac/dks141
M3 - Article
C2 - 22553141
AN - SCOPUS:84864522601
SN - 0305-7453
VL - 67
SP - 1979
EP - 1986
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 8
M1 - dks141
ER -