title: Cardamonin, a schistosomicidal chalcone from Piper aduncum L. (Piperaceae) that inhibits Schistosoma mansoni ATP diphosphohydrolase.
abstract: BACKGROUND
  Schistosomiasis is one of the world's major public health problems, and praziquantel (PZQ) is the only available drug to treat this neglected disease with an urgent demand for new drugs. Recent studies indicated that extracts from Piper aduncum L. (Piperaceae) are active against adult worms of Schistosoma mansoni, the major etiological agent of human schistosomiasis.
  
  
  OBJECTIVE
  We investigated the in vitro schistosomicidal activity of cardamonin, a chalcone isolated from the crude extract of P. aduncum. Also, this present work describes, for the first time, the S. mansoni ATP diphosphohydrolase inhibitory activity of cardamonin, as well as, its molecular docking with S. mansoni ATPDase1, in order to investigate its mode of inhibition.
  
  
  METHODS
  In vitro schistosomicidal assays and confocal laser scanning microscopy were used to evaluate the effects of cardamonin on adult schistosomes. Cell viability was measured by MTT assay, and the S. mansoni ATPase activity was determined spectrophotometrically. Identification of the cardamonin binding site and its interactions on S. mansoni ATPDase1 were made by molecular docking experiments.
  
  
  RESULTS
  A bioguided fractionation of the crude extract of P. aduncum was carried out, leading to identification of cardamonin as the active compound, along with pinocembrin and uvangoletin. Cardamonin (25, 50, and 100 µM) caused 100% mortality, tegumental alterations, and reduction of oviposition and motor activity of all adult worms of S. mansoni, without affecting mammalian cells. Confocal laser scanning microscopy showed tegumental morphological alterations and changes on the numbers of tubercles of S. mansoni worms in a dose-dependent manner. Cardamonin also inhibited S. mansoni ATP diphosphohydrolase (IC50 of 23.54 µM). Molecular docking studies revealed that cardamonin interacts with the Nucleotide-Binding of SmATPDase 1. The nature of SmATPDase 1-cardamonin interactions is mainly hydrophobic and hydrogen bonding.
  
  
  CONCLUSIONS
  This report provides evidence for the in vitro schistosomicidal activity of cardamonin and demonstrated, for the first time, that this chalcone is highly effective in inhibiting S. mansoni ATP diphosphohydrolase, opening the route to further studies of chalcones as prototypes for new S. mansoni ATP diphosphohydrolase inhibitors.
authors: Faculdade de Farmácia, Departamento de Ciências Farmacêuticas, Universidade Federal de Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil.
authors: Clarissa C B
authors: CC
authors: de Castro
authors: Faculdade de Farmácia, Departamento de Ciências Farmacêuticas, Universidade Federal de Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil.
authors: Poliana S
authors: PS
authors: Costa
authors: Faculdade de Farmácia, Departamento de Ciências Farmacêuticas, Universidade Federal de Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil.
authors: Gisele T
authors: GT
authors: Laktin
authors: Faculdade de Farmácia, Departamento de Ciências Farmacêuticas, Universidade Federal de Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil.
authors: Paulo H D
authors: PH
authors: de Carvalho
authors: Faculdade de Farmácia, Departamento de Ciências Farmacêuticas, Universidade Federal de Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil.
authors: Reinaldo B
authors: RB
authors: Geraldo
authors: Núcleo de Pesquisa em Doenças Negligenciadas (FACIG), 07025-000 Guarulhos, SP, Brazil.
authors: Josué
authors: J
authors: de Moraes
authors: Núcleo de Enteroparasitas, Instituto Adolfo Lutz, 01246-902 São Paulo, SP, Brazil.
authors: Pedro L S
authors: PL
authors: Pinto
authors: Departamento de Química, Universidade Federal de Juiz de Fora, 36036-330 Juiz de Fora, MG, Brazil.
authors: Mara R C
authors: MR
authors: Couri
authors: Instituto de Ciências Biológicas, Departamento de Bioquímica, Universidade Federal de Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil.
authors: Priscila de F
authors: Pde F
authors: Pinto
authors: Faculdade de Farmácia, Departamento de Ciências Farmacêuticas, Universidade Federal de Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil. Electronic address: ademar.alves@ufjf.edu.br.
authors: Ademar A
authors: AA
authors: Da Silva Filho
mesh_terms: D000818:Animals; D001081:Apyrase / Q000037:antagonists & inhibitors*; D047188:Chalcones / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D031701:Piper / Q000737:chemistry*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology; D012556:Schistosomicides / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D047188:Chalcones; D004791:Enzyme Inhibitors; D012556:Schistosomicides; D001081:Apyrase; C436747:cardamonin
keywords: Apyrase; Cardamom; Chalcone; Piper aduncum; Schistosomicidal activity; SmATPDases