In vitro and in vivo activity of 3-alkoxy-1,2-dioxolanes against Schistosoma mansoni

Katrin Ingram, Charles E. Schiaffo, Wantanee Sittiwong, Evan Benner, Patrick H. Dussault, Jennifer Keiser

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberdks141
Pages (from-to)1979-1986
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume67
Issue number8
DOIs
StatePublished - Aug 1 2012

Fingerprint

Dioxolanes
Schistosoma mansoni
Iron
Peroxides
Echinostoma
Pharmaceutical Preparations
Trematoda
Drug Discovery
Plasmodium falciparum
In Vitro Techniques
alkoxyl radical
Skeleton
Parasites

Keywords

  • Chemotherapy
  • Non-peroxidic analogues
  • Peroxides
  • Schistosomiasis

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

In vitro and in vivo activity of 3-alkoxy-1,2-dioxolanes against Schistosoma mansoni. / Ingram, Katrin; Schiaffo, Charles E.; Sittiwong, Wantanee; Benner, Evan; Dussault, Patrick H.; Keiser, Jennifer.

In: Journal of Antimicrobial Chemotherapy, Vol. 67, No. 8, dks141, 01.08.2012, p. 1979-1986.

Research output: Contribution to journalArticle

Ingram, Katrin ; Schiaffo, Charles E. ; Sittiwong, Wantanee ; Benner, Evan ; Dussault, Patrick H. ; Keiser, Jennifer. / In vitro and in vivo activity of 3-alkoxy-1,2-dioxolanes against Schistosoma mansoni. In: Journal of Antimicrobial Chemotherapy. 2012 ; Vol. 67, No. 8. pp. 1979-1986.
@article{8c3cd67c605b4365922e7c7eb9f22f4a,
title = "In vitro and in vivo activity of 3-alkoxy-1,2-dioxolanes against Schistosoma mansoni",
abstract = "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.",
keywords = "Chemotherapy, Non-peroxidic analogues, Peroxides, Schistosomiasis",
author = "Katrin Ingram and Schiaffo, {Charles E.} and Wantanee Sittiwong and Evan Benner and Dussault, {Patrick H.} and Jennifer Keiser",
year = "2012",
month = "8",
day = "1",
doi = "10.1093/jac/dks141",
language = "English (US)",
volume = "67",
pages = "1979--1986",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "8",

}

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

PY - 2012/8/1

Y1 - 2012/8/1

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

UR - http://www.scopus.com/inward/record.url?scp=84864522601&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864522601&partnerID=8YFLogxK

U2 - 10.1093/jac/dks141

DO - 10.1093/jac/dks141

M3 - Article

C2 - 22553141

AN - SCOPUS:84864522601

VL - 67

SP - 1979

EP - 1986

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 8

M1 - dks141

ER -