title: Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice.
abstract: Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Masic
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Valencia Hernandez
authors.affiliation: Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Hazra
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Glaser
authors.affiliation: Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.affiliation: Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
authors.forename: Banasri
authors.initials: B
authors.lastname: Hazra
authors.affiliation: Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Schurigt
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007891:Leishmania; D007896:Leishmaniasis / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D014632:Valerian
chemical_list: D000981:Antiprotozoal Agents; D002934:Cinnamates; D010936:Plant Extracts; C029010:cinnamic acid