New praziquantel derivatives containing NO-donor furoxans and related furazans as active agents against Schistosoma mansoni

Eur J Med Chem. 2014 Sep 12;84:135-45. doi: 10.1016/j.ejmech.2014.07.007. Epub 2014 Jul 3.

Abstract

A series of NO-donor praziquantel hybrid compounds was obtained by combining praziquantel (PZQ) and furoxan moieties in a single entity. NO-donor properties of the furoxan derivatives were evaluated by detecting nitrite after incubation of the products in 7.4 pH buffered solution in the presence of L-cysteine. Structurally-related furazans, devoid of NO release capacity, were also synthesized for control purposes. All products were studied for their ability to inhibit recombinant Schistosoma mansoni thioredoxin glutathione reductase (TGR). Mobility and death of adult Schistosoma mansoni worms cultured in the presence of the products were evaluated versus PZQ. Analysis of the results showed that some products were endowed with both PZQ and NO-dependent antiparasitic properties. Compounds 6, 7, 18, and 24 emerged as the most interesting balanced hybrids, worthy of additional study on PZQ-resistant parasites.

Keywords: Furoxans; NO-donor praziquantel; Praziquantel; Schistosomiasis; Thioredoxin glutathione reductase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Isoquinolines / chemistry*
  • Molecular Structure
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors
  • NADH, NADPH Oxidoreductases / metabolism
  • Nitric Oxide / chemistry
  • Nitric Oxide Donors / chemistry*
  • Oxadiazoles / chemistry*
  • Praziquantel / chemical synthesis
  • Praziquantel / chemistry
  • Praziquantel / pharmacology*
  • Pyrazines / chemistry*
  • Schistosoma mansoni / drug effects*
  • Schistosoma mansoni / enzymology
  • Schistosoma mansoni / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoquinolines
  • Multienzyme Complexes
  • Nitric Oxide Donors
  • Oxadiazoles
  • Pyrazines
  • furoxans
  • Nitric Oxide
  • Praziquantel
  • NADH, NADPH Oxidoreductases
  • thioredoxin glutathione reductase