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 language | English |
|---|---|
| Pages (from-to) | 35-43 |
| Number of pages | 9 |
| Journal | International Journal for Parasitology: Drugs and Drug Resistance |
| Volume | 9 |
| Early online date | 14 Jan 2019 |
| DOIs | |
| Publication status | Published - Apr 2019 |
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Keywords
- In vitro drug screening
- Mouse model
- Phosphodiesterase
- Praziquantel
- Schistosoma mansoni
- Schistosomiasis
- Worm killing
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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 Journal › Article › Academic › peer-review
TY - JOUR
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
Y1 - 2019/4
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.
AB - 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.
KW - In vitro drug screening
KW - Mouse model
KW - Phosphodiesterase
KW - Praziquantel
KW - Schistosoma mansoni
KW - Schistosomiasis
KW - Worm killing
UR - http://www.scopus.com/inward/record.url?scp=85060094840&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060094840&partnerID=8YFLogxK
U2 - 10.1016/j.ijpddr.2019.01.001
DO - 10.1016/j.ijpddr.2019.01.001
M3 - Article
VL - 9
SP - 35
EP - 43
JO - International Journal for Parasitology: Drugs and Drug Resistance
JF - International Journal for Parasitology: Drugs and Drug Resistance
SN - 2211-3207
ER -