title: Synergistic effects of in vitro combinations of piplartine, epiisopiloturine and praziquantel against Schistosoma mansoni.
abstract: Schistosomiasis is a world health problem, and praziquantel is the only drug currently used for the treatment. There is some evidence that extensive monotherapy of praziquantel may be leading to drug resistance in the parasite. In order to find alternative treatments, the effects of the combination of epiisopiloturine (EPI), piplartine (PPT) and praziquantel (PZQ) were evaluated. Similarity analysis of these compounds was performed using optimized molecular structures to compare the shape and the charge modeling of combinations between PZQ and EPI or PPT. Supported by this data, in vitro association of PZQ-PPT, PZQ-EPI, and EPI-PPT was carried out, and the activity of these combinations against Schistosoma mansoni was assessed. The results showed synergistic activity with a combination index (CI) of 0.42 for the treatment with PZQ-PPT. Both PZQ-EPI and EPI-PPT combinations also showed synergistic effects, with CI values of 0.86 and 0.61, respectively. Surface alterations in the tegument of adult schistosomes after the treatments were observed using laser confocal microscopy and scanning electron microscopy. Additionally, the association of EPI-PPT decreased the cytotoxicity when compared with both isolated compounds in three different lines of mammalian cells. Thus, synergistic combinations of PZQ-PPT, PZQ-EPI, and EPI-PPT create the possibility of reduced doses to be used against Schistosoma mansoni.
authors.affiliation: Biodiversity and Biotechnology Research Center, Biotec, Federal University of Piauí, UFPI, Parnaíba, PI, 64202020, Brazil; Institute of Higher Education of Vale do Parnaíba, FAHESP/IESVAP, Parnaíba, PI, Brazil.
authors.forename: Yuri Dias Macedo
authors.initials: YDM
authors.lastname: Campelo
authors.affiliation: São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Mafud
authors.affiliation: Biodiversity and Biotechnology Research Center, Biotec, Federal University of Piauí, UFPI, Parnaíba, PI, 64202020, Brazil.
authors.forename: Leiz Maria Costa
authors.initials: LMC
authors.lastname: Véras
authors.affiliation: Biodiversity and Biotechnology Research Center, Biotec, Federal University of Piauí, UFPI, Parnaíba, PI, 64202020, Brazil; Phytobios Nordeste LTDA, Centroflora Group, Parnaíba, PI, Brazil.
authors.forename: Maria Adelaide
authors.initials: MA
authors.lastname: Guimarães
authors.affiliation: Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Lydia F
authors.initials: LF
authors.lastname: Yamaguchi
authors.affiliation: Biodiversity and Biotechnology Research Center, Biotec, Federal University of Piauí, UFPI, Parnaíba, PI, 64202020, Brazil; Federal University of Vale do São Francisco, Paulo Afonso, BA, Brazil.
authors.forename: David Fernandes
authors.initials: DF
authors.lastname: Lima
authors.affiliation: Biodiversity and Biotechnology Research Center, Biotec, Federal University of Piauí, UFPI, Parnaíba, PI, 64202020, Brazil.
authors.forename: Daniel Dias Rufino
authors.initials: DDR
authors.lastname: Arcanjo
authors.affiliation: Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Massuo J
authors.initials: MJ
authors.lastname: Kato
authors.affiliation: Laboratory of Parasitology, Butantan Institute, São Paulo, SP, Brazil.
authors.forename: Ronaldo Z
authors.initials: RZ
authors.lastname: Mendonça
authors.affiliation: Enteroparasites Center, Adolfo Lutz Institute, São Paulo, SP, Brazil.
authors.forename: Pedro Luiz Silva
authors.initials: PLS
authors.lastname: Pinto
authors.affiliation: São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.
authors.forename: Yvonne Primerano
authors.initials: YP
authors.lastname: Mascarenhas
authors.affiliation: Research Center for Neglected Diseases, Guarulhos University, Guarulhos, SP, Brazil.
authors.forename: Marcos P N
authors.initials: MPN
authors.lastname: Silva
authors.affiliation: Research Center for Neglected Diseases, Guarulhos University, Guarulhos, SP, Brazil.
authors.forename: Josué
authors.initials: J
authors.lastname: de Moraes
authors.affiliation: Biodiversity and Biotechnology Research Center, Biotec, Federal University of Piauí, UFPI, Parnaíba, PI, 64202020, Brazil; UCIBIO/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Portugal.
authors.forename: Peter
authors.initials: P
authors.lastname: Eaton
authors.affiliation: Biodiversity and Biotechnology Research Center, Biotec, Federal University of Piauí, UFPI, Parnaíba, PI, 64202020, Brazil; Faculty of Medicine, University of Brasilia, UnB, Brasília, DF, Brazil. Electronic address: jrsaleite@gmail.com.
authors.forename: José Roberto
authors.initials: JR
authors.lastname: de Souza de Almeida Leite
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D048430:Cell Shape / Q000187:drug effects; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D011223:Praziquantel / Q000737:chemistry / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000648:ultrastructure; D014709:Vero Cells
chemical_list: D000981:Antiprotozoal Agents; D007093:Imidazoles; D010881:Piperidones; C575691:epiisopiloturine; C498077:piperlongumine; D011223:Praziquantel; D015107:4-Butyrolactone
keywords: Alkaloid; Drug combination; Druglikeness; Epiisopiloturine; Pilocarpus microphyllus; Piplartine; Praziquantel; Schistosoma mansoni