title: New praziquantel derivatives containing NO-donor furoxans and related furazans as active agents against Schistosoma mansoni.
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.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università of Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guglielmo
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università of Torino, Via P. Giuria 9, 10125 Torino, Italy; Department of Immunology/Microbiology, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cortese
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università of Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Vottero
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università of Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA.
authors.forename: Valerie P
authors.initials: VP
authors.lastname: Kommer
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA. Electronic address: david_l_williams@rush.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università of Torino, Via P. Giuria 9, 10125 Torino, Italy. Electronic address: roberta.fruttero@unito.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università of Torino, Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000737:chemistry*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry; D020030:Nitric Oxide Donors / Q000737:chemistry*; D010069:Oxadiazoles / Q000737:chemistry*; D011223:Praziquantel / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009097:Multienzyme Complexes; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011719:Pyrazines; C010166:furoxans; D009569:Nitric Oxide; D011223:Praziquantel; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase
keywords: Furoxans; NO-donor praziquantel; Praziquantel; Schistosomiasis; Thioredoxin glutathione reductase