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

Botros, S. S. et al. (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, pp. 35-43. (doi:10.1016/j.ijpddr.2019.01.001)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Munday, Dr Jane and De Koning, Professor Harry
Authors: Botros, S. S., William, S., Sabra, A.-N. A., El-Lakkany, N. M., Seif el-Din, S. H., García-Rubia, A., Sebastián-Pérez, V., Blaazer, A. R., de Heuvel, E., Sijm, M., Zheng, Y., Salado, I. G., Munday, J. C., Maes, L., de Esch, I. J.P., Sterk, G. J., Augustyns, K., Leurs, R., Gil, C., and De Koning, H. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:International Journal for Parasitology: Drugs and Drug Resistance
Publisher:Elsevier
ISSN:2211-3207
ISSN (Online):2211-3207
Published Online:14 January 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in International Journal for Parasitology: Drugs and Drug Resistance 9: 35-43
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620151PDE4NTD: Phosphodieasease inhibitors for the treatment of Neglected Parasitic Diseases.Harry De KoningEuropean Commission (EC)602666III - PARASITOLOGY