title: Natural products from Zanthoxylum heitzii with potent activity against the malaria parasite.
abstract: Zanthoxylum heitzii (Rutaceae) (olon) is used in traditional medicine in Central and West Africa to treat malaria. To identify novel compounds with anti-parasitic activity and validate medicinal usage, extracts and compounds isolated from this tree were tested against the erythrocytic stages of the human malaria parasite Plasmodium falciparum and for inhibition of transmission in rodent malaria parasite Plasmodium berghei.
  
  
  
  Hexane bark extract showed activity against P. falciparum (IC50 0.050 μg/ml), while leaf and seed extracts were inactive. Fractionation of the hexane bark extract led to the identification of three active constituents; dihydronitidine, pellitorine and heitziquinone. Dihydronitidine was the most active compound with an IC50 value of 0.0089 µg/ml (25 nM). This compound was slow acting, requiring 50 % longer exposure time than standard anti-malarials to reach full efficacy. Heitziquinone and pellitorine were less potent, with IC50 values of 3.55 μg/ml and 1.96 µg/ml, but were fast-acting. Plasmodium berghei ookinete conversion was also inhibited by the hexane extract (IC50 1.75 µg/ml), dihydronitidine (0.59 µg/ml) and heitziquinone (6.2 µg/ml). Water extracts of Z. heitzii bark contain only low levels of dihydronitidine and show modest anti-parasitic activity.
  
  
  
  Three compounds with anti-parasitic activity were identified in Z. heitzii bark extract. The alkaloid dihydronitidine is the most effective of these, accounting for the bulk of activity in both erythrocytic and transmission-blocking assays. These compounds may present good leads for development of novel anti-malarials and add to the understanding of the chemical basis of the anti-parasitic activity in these classes of natural product.
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Christopher Dean
authors.initials: CD
authors.lastname: Goodman
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P. O. Box 1068, Blindern, 0316, Oslo, Norway.
authors.forename: Ingvild
authors.initials: I
authors.lastname: Austarheim
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mollard
authors.affiliation: National Polytechnic High School, Marien Ngouabi University, BP 69, Brazzaville, Republic of Congo.
authors.forename: Bertin
authors.initials: B
authors.lastname: Mikolo
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P. O. Box 1068, Blindern, 0316, Oslo, Norway.
authors.forename: Karl Egil
authors.initials: KE
authors.lastname: Malterud
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, VIC, 3010, Australia.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: McFadden
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, P. O. Box 1068, Blindern, 0316, Oslo, Norway. helle.wangensteen@farmasi.uio.no.
authors.forename: Helle
authors.initials: H
authors.lastname: Wangensteen
mesh_terms: D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D032106:Zanthoxylum / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D001688:Biological Products
keywords: Anti-malarial; Benzophenanthridine alkaloid; Dihydronitidine; Ethnobotany; Malaria; Ookinete; Rutaceae; Transmission blocking; Zanthoxylum heitzii