TY - JOUR A1 - Masic, Anita A1 - Valencia Hernandez, Ana Maria A1 - Hazra, Sudipta A1 - Glaser, Jan A1 - Holzgrabe, Ulrike A1 - Hazra, Banasri A1 - Schurigt, Uta T1 - Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice JF - PLoS One N2 - 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. KW - leishmania major KW - promastigotes KW - apoptosis KW - mitochondria KW - parasitic diseases KW - leishmania KW - leishmaniasis KW - mouse models Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125354 VL - 10 IS - 11 ER - TY - JOUR A1 - Glaser, Jan A1 - Schurigt, Uta A1 - Suzuki, Brian M. A1 - Caffrey, Connor R. A1 - Holzgrabe, Ulrike T1 - Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl JF - Molecules N2 - Bornyl caffeate (1) was previously isolated by us from Valeriana (V.) wallichii rhizomes and identified as an anti-leishmanial substance. Here, we screened a small compound library of synthesized derivatives 1–30 for activity against schistosomula of Schistosoma (S.) mansoni. Compound 1 did not show any anti-schistosomal activity. However, strong phenotypic changes, including the formation of vacuoles, degeneration and death were observed after in vitro treatment with compounds 23 (thymyl cinnamate) and 27 (eugenyl cinnamate). Electron microscopy analysis of the induced vacuoles in the dying parasites suggests that 23 and 27 interfere with autophagy. KW - thymyl cinnamate KW - vacuoles KW - autophagy KW - anti-schistosomal activity KW - schistosoma KW - schistosomula KW - parasite KW - eugenyl cinnamate Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125712 VL - 20 ER - TY - JOUR A1 - Glaser, Jan A1 - Schultheis, Martina A1 - Moll, Heidrun A1 - Hazra, Banasri A1 - Holzgrabe, Ulrike T1 - Antileishmanial and Cytotoxic Compounds from Valeriana wallichii and Identification of a Novel Nepetolactone Derivative JF - Molecules N2 - The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives 2–3 with moderate leishmanicidal activity. The structure of a novel nepetolactone derivative 4 having a cinnamic acid moiety was elucidated by means of spectral analysis. To the best of our knowledge villoside aglycone (5) was isolated from this plant for the first time. The bioassay-guided fractionation yielded two new (compounds 6–7) and two known valtrates (compounds 8–9) with leishmanicidal potential against Leishmania major (L. major) promastigotes. In addition, β-bisabolol (10), α-kessyl alcohol (11), valeranone (12), bornyl isovalerate (13) and linarin-2-O-methylbutyrate (14) were identified. This is the first report on the isolation of 4'-demethylpodophyllotoxin (15), podophyllotoxin (16) and pinoresinol (17) in V. wallichii. In total thirteen known and four new compounds were identified from the extract and their cytotoxic and antileishmanial properties were evaluated. KW - novel nepetolactone derivative KW - cytotoxicity KW - antileishmanial KW - V. wallichii KW - podophyllotoxin KW - valtrates Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125320 VL - 20 IS - 4 ER - TY - THES A1 - Glaser, Jan T1 - Antileishmanial compounds from Nature - Elucidation of the active principles of an extract from Valeriana wallichii rhizomes T1 - Antileishmaniale Wirkstoffe aus der Natur - Aufklärung des Wirkprinzips eines Wurzelextraktes von Valeriana wallichii N2 - This study is dealing with the bioactivity-guided fractionation of a chloroform extract from pulverized rhizomes of Valeriana wallichii with focus on isolation and structure elucidation of the antileishmanial active principles. N2 - Die vorliegende Studie beschäftigt sich mit der bioaktivitätsgeleiteten Fraktionierung eines Chloroformextraktes aus pulverisierten Rhizomen von Valeriana wallichii mit Schwerpunkt auf der Isolierung und Strukturaufklärung des antileishmanialen Wirkprinzips. KW - Leishmaniose KW - Valeriana wallichii KW - Extrakt KW - Rhizom KW - Naturstoff KW - natural products KW - antileishmanial KW - Valeriana wallichii Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129140 ER - TY - JOUR A1 - Glaser, Jan A1 - Schultheis, Martina A1 - Hazra, Sudipta A1 - Hazra, Banazri A1 - Moll, Heidrun A1 - Schurigt, Uta A1 - Holzgrabe, Ulrike T1 - Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester N2 - Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization KW - Valeriana wallichii KW - leishmaniasis KW - caffeic acid bornyl ester KW - structure-activity relationship Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112835 ER -