Activities of N,N′-Diarylurea MMV665852 Analogs against Schistosoma mansoni

Noemi Cowan, Philipp Dätwyler, Beat Ernst, Chunkai Wang, Jonathan L Vennerstrom, Thomas Spangenberg, Jennifer Keiser

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

There is an unmet need to discover and develop novel antischistosomal drugs. As exemplified by MMV665852, N,N'-diarylureas have recently emerged as a promising antischistosomal chemotype. In this study, we evaluated the structure-activity relationships of 46 commercially available analogs of MMV665852 on newly transformed schistosomula (NTS) and adult Schistosoma mansoni worms in vitro. Active compounds were evaluated with a cytotoxicity assay, in silico calculations, metabolic stability studies, and an in vivo assay with mice harboring adult S. mansoni worms. Of the 46 compounds tested at 33.3 μM, 13 and 14 compounds killed NTS and adult worms, respectively, within 72 h. Nine compounds had 90% inhibitory concentrations (IC90s) of ≤ 10 μMagainst adult worms, with selectivity indexes of ≥ 2.8. Their physicochemical properties and permeation through an artificial membrane indicated good to moderate intestinal absorption. Their metabolic stabilities ranged from low to high. Despite satisfactory in vitro results and in silico predictions, only one compound resulted in a statistically significant worm burden reduction (66%) after administration of a single oral dose of 400 mg/kg of body weight to S. mansoni-infected mice. Worm burden reductions of 0 to 43% were observed for the remaining eight compounds tested. In conclusion, several analogs of the N,N'-diarylurea MMV665852 had high efficacy against S. mansoni in vitro and favorable physicochemical properties for permeation through the intestinal wall. To counteract the low efficacy observed in the mouse model, further investigations should focus on identifying compounds with improved solubility and pharmacokinetic properties.

Original languageEnglish (US)
Pages (from-to)1935-1941
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number4
DOIs
StatePublished - Apr 1 2015

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Schistosoma mansoni
Computer Simulation
Artificial Membranes
Intestinal Absorption
Structure-Activity Relationship
Solubility
Pharmacokinetics
Body Weight
MMV665852
Pharmaceutical Preparations
In Vitro Techniques

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Activities of N,N′-Diarylurea MMV665852 Analogs against Schistosoma mansoni. / Cowan, Noemi; Dätwyler, Philipp; Ernst, Beat; Wang, Chunkai; Vennerstrom, Jonathan L; Spangenberg, Thomas; Keiser, Jennifer.

In: Antimicrobial Agents and Chemotherapy, Vol. 59, No. 4, 01.04.2015, p. 1935-1941.

Research output: Contribution to journalArticle

Cowan, N, Dätwyler, P, Ernst, B, Wang, C, Vennerstrom, JL, Spangenberg, T & Keiser, J 2015, 'Activities of N,N′-Diarylurea MMV665852 Analogs against Schistosoma mansoni', Antimicrobial Agents and Chemotherapy, vol. 59, no. 4, pp. 1935-1941. https://doi.org/10.1128/AAC.04463-14
Cowan, Noemi ; Dätwyler, Philipp ; Ernst, Beat ; Wang, Chunkai ; Vennerstrom, Jonathan L ; Spangenberg, Thomas ; Keiser, Jennifer. / Activities of N,N′-Diarylurea MMV665852 Analogs against Schistosoma mansoni. In: Antimicrobial Agents and Chemotherapy. 2015 ; Vol. 59, No. 4. pp. 1935-1941.
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