title: Evaluation of antiplasmodial and antileishmanial activities of herbal medicine Pseudelephantopus spiralis (Less.) Cronquist and isolated hirsutinolide-type sesquiterpenoids.
abstract: BACKGROUND
  Pseudelephantopus spiralis (Less.) Cronquist is distributed in the Caribbean, Mesoamerica and Latin America. Preparations of the plant are traditionally used in Latin America for the treatment of various diseases including fever, malaria, and spleen or liver inflammations.
  
  
  METHODS
  Aerial parts of P. spiralis were extracted with either ethanol or distilled water. Seven hirsutinolide-type sesquiterpenoids were isolated: 8-acetyl-13-ethoxypiptocarphol (1), diacetylpiptocarphol (2), piptocarphins A (3), F (4) and D (5), (1S(*),4R(*),8S(*),10R(*))-1,4-epoxy-13-ethoxy-1,8,10-trihydroxygermacra-5E,7(11)-dien-6,12-olide (6), and piptocarphol (7). Extracts and isolated compounds (2, 3, 5-7) were screened for their in vitro antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FcM29-Cameroon and antileishmanial activity against three stages of Leishmania infantum. Their cytotoxicities were also evaluated against healthy VERO cell lines and J774A.1 macrophages, the host cells of the Leishmania parasites in humans.
  
  
  RESULTS
  Aqueous extracts showed a greater inhibitory effect than alcoholic extracts, with IC50 on P. falciparum of 3.0µg/mL versus 21.1µg/mL, and on L. infantum of 13.4µg/mL versus >50µg/mL. Both extracts were found to be cytotoxic to VERO cells (CC50<3µg/mL). Sesquiterpene lactones 2 and 3 showed the best activity against both parasites but failed in selectivity. Carbon 8 hydroxylated hirsutinolides 5-7 presented the particularity of exhibiting two conformers observed in solution during extensive NMR analyses in CD3OD and UHPLC-MS. The presence of a hydroxyl function at C-8 decreased the activity of 5-7 on the two parasites and also on VERO cells.
  
  
  CONCLUSIONS
  The antiplasmodial activity displayed by the aqueous extract explains the traditional use of P. spiralis in the treatment of malaria. This activity seems to be attributable to the presence of sesquiterpene lactones 2 and 3, the most active against P. falciparum. Aqueous extract and compounds 2, 3 and 6 were also active against L. infantum but lacked in selectivity due to their cytotoxicity towards macrophages. Exploring the safety and antiplasmodial efficacy of this traditional remedy will require further toxicological and in vivo studies in the light of the cytotoxicity towards healthy cell lines displayed by the aqueous extract and compounds 2 and 3.
authors.affiliation: Université de Toulouse, UPS, UMR 152 Pharma-DEV, Université Toulouse 3, Faculté des Sciences Pharmaceutiques, F-31062 Toulouse Cedex 09, France; Institut de Recherche pour le Développement (IRD), UMR 152 Pharma-DEV, F-31062 Toulouse Cedex 09, France.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Girardi
authors.affiliation: Université de Toulouse, UPS, UMR 152 Pharma-DEV, Université Toulouse 3, Faculté des Sciences Pharmaceutiques, F-31062 Toulouse Cedex 09, France; Institut de Recherche pour le Développement (IRD), UMR 152 Pharma-DEV, F-31062 Toulouse Cedex 09, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fabre
authors.affiliation: Université de Toulouse, UPS, UMR 152 Pharma-DEV, Université Toulouse 3, Faculté des Sciences Pharmaceutiques, F-31062 Toulouse Cedex 09, France; Institut de Recherche pour le Développement (IRD), UMR 152 Pharma-DEV, F-31062 Toulouse Cedex 09, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Paloque
authors.affiliation: CNRS, LCC (Laboratoire de Chimie de Coordination) UPR 8241, 31077 Toulouse Cedex 4, France; Université de Toulouse, UPS, INPT, 31077 Toulouse Cedex 4, France.
authors.forename: Arba Pramundita
authors.initials: AP
authors.lastname: Ramadani
authors.affiliation: CNRS, LCC (Laboratoire de Chimie de Coordination) UPR 8241, 31077 Toulouse Cedex 4, France; Université de Toulouse, UPS, INPT, 31077 Toulouse Cedex 4, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
authors.affiliation: Université de Toulouse, UPS, UMR 152 Pharma-DEV, Université Toulouse 3, Faculté des Sciences Pharmaceutiques, F-31062 Toulouse Cedex 09, France; Institut de Recherche pour le Développement (IRD), UMR 152 Pharma-DEV, F-31062 Toulouse Cedex 09, France.
authors.forename: German
authors.initials: G
authors.lastname: González-Aspajo
authors.affiliation: Université de Toulouse, UPS, UMR 152 Pharma-DEV, Université Toulouse 3, Faculté des Sciences Pharmaceutiques, F-31062 Toulouse Cedex 09, France; Institut de Recherche pour le Développement (IRD), UMR 152 Pharma-DEV, F-31062 Toulouse Cedex 09, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Haddad
authors.affiliation: Programa de Investigación en Biodiversidad Amazónica (PIBA). Instituto de Investigaciones de la Amazonía Peruana-IIAP, Av. Abelardo Quiñones km 4.5, Iquitos, Peru.
authors.forename: Elsa
authors.initials: E
authors.lastname: Rengifo
authors.affiliation: Université de Toulouse, UPS, UMR 152 Pharma-DEV, Université Toulouse 3, Faculté des Sciences Pharmaceutiques, F-31062 Toulouse Cedex 09, France; Institut de Recherche pour le Développement (IRD), UMR 152 Pharma-DEV, Mission IRD, Casilla 18-1209, Lima, Peru. Electronic address: valerie.jullian@ird.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Jullian
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D019659:Asteraceae / Q000737:chemistry*; D002460:Cell Line; D002522:Chlorocebus aethiops; D020128:Inhibitory Concentration 50; D018314:Leishmania infantum / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008519:Medicine, Traditional; D051379:Mice; D035261:Plant Components, Aerial; D010936:Plant Extracts / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D000962:Antimalarials; D000981:Antiprotozoal Agents; D010936:Plant Extracts; D012717:Sesquiterpenes
keywords: Hirsutinolides; Leishmaniasis; Malaria; Pseudelephantopus spiralis; Sesquiterpene lactones