Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity

Sanaa S. Botros, Samia William, Abdel Nasser A. Sabra, Naglaa M. El-Lakkany, Sayed H. Seif el-Din, Alfonso García-Rubia, Victor Sebastián-Pérez, Antoni R. Blaazer, Erik de Heuvel, Maarten Sijm, Yang Zheng, Irene G. Salado, Jane C. Munday, Louis Maes, Iwan J.P. de Esch, Geert J. Sterk, Koen Augustyns, Rob Leurs, Carmen Gil, Harry P. De Koning

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

We report the evaluation of 265 compounds from a PDE-focused library for their antischistosomal activity, assessed in vitro using Schistosoma mansoni. Of the tested compounds, 171 (64%) displayed selective in vitro activity, with 16 causing worm hypermotility/spastic contractions and 41 inducing various degrees of worm killing at 100 μM, with the surviving worms displaying sluggish movement, worm unpairing and complete absence of eggs. The compounds that did not affect worm viability (n = 72) induced a complete cessation of ovipositing. 82% of the compounds had an impact on male worms whereas female worms were barely affected. In vivo evaluation in S. mansoni-infected mice with the in vitro ‘hit’ NPD-0274 at 20 mg/kg/day orally for 5 days resulted in worm burden reductions of 29% and intestinal tissue egg load reduction of 35% at 10 days post-treatment. Combination of praziquantel (PZQ) at 10 mg/kg/day for 5 days with NPD-0274 or NPD-0298 resulted in significantly higher worm killing than PZQ alone, as well as a reduction in intestinal tissue egg load, disappearance of immature eggs and an increase in the number of dead eggs.

Original languageEnglish
Pages (from-to)35-43
Number of pages9
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume9
Early online date14 Jan 2019
DOIs
Publication statusPublished - Apr 2019

Fingerprint

Imidazoles
Eggs
Libraries
Praziquantel
Schistosoma mansoni
Ovum
Muscle Spasticity
In Vitro Techniques
neodymium pyrocatechin disulfonate

Keywords

  • In vitro drug screening
  • Mouse model
  • Phosphodiesterase
  • Praziquantel
  • Schistosoma mansoni
  • Schistosomiasis
  • Worm killing

Cite this

Botros, S. S., William, S., Sabra, A. N. A., El-Lakkany, N. M., Seif el-Din, S. H., García-Rubia, A., ... De Koning, H. P. (2019). Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity. International Journal for Parasitology: Drugs and Drug Resistance, 9, 35-43. https://doi.org/10.1016/j.ijpddr.2019.01.001
Botros, Sanaa S. ; William, Samia ; Sabra, Abdel Nasser A. ; El-Lakkany, Naglaa M. ; Seif el-Din, Sayed H. ; García-Rubia, Alfonso ; Sebastián-Pérez, Victor ; Blaazer, Antoni R. ; de Heuvel, Erik ; Sijm, Maarten ; Zheng, Yang ; Salado, Irene G. ; Munday, Jane C. ; Maes, Louis ; de Esch, Iwan J.P. ; Sterk, Geert J. ; Augustyns, Koen ; Leurs, Rob ; Gil, Carmen ; De Koning, Harry P. / Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity. In: International Journal for Parasitology: Drugs and Drug Resistance. 2019 ; Vol. 9. pp. 35-43.
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abstract = "We report the evaluation of 265 compounds from a PDE-focused library for their antischistosomal activity, assessed in vitro using Schistosoma mansoni. Of the tested compounds, 171 (64{\%}) displayed selective in vitro activity, with 16 causing worm hypermotility/spastic contractions and 41 inducing various degrees of worm killing at 100 μM, with the surviving worms displaying sluggish movement, worm unpairing and complete absence of eggs. The compounds that did not affect worm viability (n = 72) induced a complete cessation of ovipositing. 82{\%} of the compounds had an impact on male worms whereas female worms were barely affected. In vivo evaluation in S. mansoni-infected mice with the in vitro ‘hit’ NPD-0274 at 20 mg/kg/day orally for 5 days resulted in worm burden reductions of 29{\%} and intestinal tissue egg load reduction of 35{\%} at 10 days post-treatment. Combination of praziquantel (PZQ) at 10 mg/kg/day for 5 days with NPD-0274 or NPD-0298 resulted in significantly higher worm killing than PZQ alone, as well as a reduction in intestinal tissue egg load, disappearance of immature eggs and an increase in the number of dead eggs.",
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author = "Botros, {Sanaa S.} and Samia William and Sabra, {Abdel Nasser A.} and El-Lakkany, {Naglaa M.} and {Seif el-Din}, {Sayed H.} and Alfonso Garc{\'i}a-Rubia and Victor Sebasti{\'a}n-P{\'e}rez and Blaazer, {Antoni R.} and {de Heuvel}, Erik and Maarten Sijm and Yang Zheng and Salado, {Irene G.} and Munday, {Jane C.} and Louis Maes and {de Esch}, {Iwan J.P.} and Sterk, {Geert J.} and Koen Augustyns and Rob Leurs and Carmen Gil and {De Koning}, {Harry P.}",
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Botros, SS, William, S, Sabra, ANA, El-Lakkany, NM, Seif el-Din, SH, García-Rubia, A, Sebastián-Pérez, V, Blaazer, AR, de Heuvel, E, Sijm, M, Zheng, Y, Salado, IG, Munday, JC, Maes, L, de Esch, IJP, Sterk, GJ, Augustyns, K, Leurs, R, Gil, C & De Koning, HP 2019, 'Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity' International Journal for Parasitology: Drugs and Drug Resistance, vol. 9, pp. 35-43. https://doi.org/10.1016/j.ijpddr.2019.01.001

Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity. / Botros, Sanaa S.; William, Samia; Sabra, Abdel Nasser A.; El-Lakkany, Naglaa M.; Seif el-Din, Sayed H.; García-Rubia, Alfonso; Sebastián-Pérez, Victor; Blaazer, Antoni R.; de Heuvel, Erik; Sijm, Maarten; Zheng, Yang; Salado, Irene G.; Munday, Jane C.; Maes, Louis; de Esch, Iwan J.P.; Sterk, Geert J.; Augustyns, Koen; Leurs, Rob; Gil, Carmen; De Koning, Harry P.

In: International Journal for Parasitology: Drugs and Drug Resistance, Vol. 9, 04.2019, p. 35-43.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity

AU - Botros, Sanaa S.

AU - William, Samia

AU - Sabra, Abdel Nasser A.

AU - El-Lakkany, Naglaa M.

AU - Seif el-Din, Sayed H.

AU - García-Rubia, Alfonso

AU - Sebastián-Pérez, Victor

AU - Blaazer, Antoni R.

AU - de Heuvel, Erik

AU - Sijm, Maarten

AU - Zheng, Yang

AU - Salado, Irene G.

AU - Munday, Jane C.

AU - Maes, Louis

AU - de Esch, Iwan J.P.

AU - Sterk, Geert J.

AU - Augustyns, Koen

AU - Leurs, Rob

AU - Gil, Carmen

AU - De Koning, Harry P.

PY - 2019/4

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N2 - We report the evaluation of 265 compounds from a PDE-focused library for their antischistosomal activity, assessed in vitro using Schistosoma mansoni. Of the tested compounds, 171 (64%) displayed selective in vitro activity, with 16 causing worm hypermotility/spastic contractions and 41 inducing various degrees of worm killing at 100 μM, with the surviving worms displaying sluggish movement, worm unpairing and complete absence of eggs. The compounds that did not affect worm viability (n = 72) induced a complete cessation of ovipositing. 82% of the compounds had an impact on male worms whereas female worms were barely affected. In vivo evaluation in S. mansoni-infected mice with the in vitro ‘hit’ NPD-0274 at 20 mg/kg/day orally for 5 days resulted in worm burden reductions of 29% and intestinal tissue egg load reduction of 35% at 10 days post-treatment. Combination of praziquantel (PZQ) at 10 mg/kg/day for 5 days with NPD-0274 or NPD-0298 resulted in significantly higher worm killing than PZQ alone, as well as a reduction in intestinal tissue egg load, disappearance of immature eggs and an increase in the number of dead eggs.

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KW - In vitro drug screening

KW - Mouse model

KW - Phosphodiesterase

KW - Praziquantel

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KW - Schistosomiasis

KW - Worm killing

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